Benzamidoaldehydes and their use as cysteine protease inhibitors

ABSTRACT

Compounds of the formula                    
     where R 1 , R 2 , R 3 , X and n are as defined in the description, are inhibitors of cysteine protease.

This application is the national phase of PCT/EP97/06292, filed Nov. 11,1997.

The present invention relates to novel benzamidoaldehydes and to theirapplication for controlling disorders.

Calpains are intracellular proteolytic enzymes of the group of thecysteine proteases and are found in many cells. Calpains are activatedby elevated calcium concentrations, a distinction being made betweencalpain I or micro-calpain, which is activated by micro-molarconcentrations of calcium ions, and calpain II or m-calpain, which isactivated by m-molar concentrations of calcium ions (P. Johnson,Int.J.Biochem. 22(8) 1990, 811-22). Further calpain isoenzymes are nowbeing postulated (K. Suzuki et al., Biol.Chem. Hoppe-Seyler, 376(9)(1995), 523-9).

Calpains are thought to play an important role in various physiologicalprocesses. These include: the cleavage of regulatory proteins—such asprotein kinase C, cytoskeletal proteins (such as MAP 2 and spectrin),muscular proteins, proteins involved in the activation of platelets,proteins involved in mitosis and others which are listed in M. J.Barrett et al., Life Sci. 48 (1991), 1659-69 and K. K. Wang et al.,Trends in Pharmacol.Sci., 15 (1994), 412-9; protein breakdown inrheumatoid arthritis and neuropeptide metabolism.

Elevated calpain levels were detected in various pathophysiologicalprocesses, for example, ischemia of the heart (for example myocardialinfarction), the kidney or the central nervous system (for examplestroke), inflammations, muscular dystrophies, cataracts of the eyes,injuries of the central nervous system (for example trauma) andAlzheimer's disease (see K. K. Wang, above). It is therefore assumedthat these disorders are linked to increased intracellular calciumlevels. Owing to this, calcium-dependent processes are overactivated andno longer subject to physiological regulation. Accordingly, anoveractivation of calpains can also cause pathophysiological processes.

It has therefore been postulated that inhibitors of calpain enzymes maybe useful for the treatment of these disorders. This has been confirmedby various studies. Thus, Seung-Chyul Hong et al., Stroke 25 (3) (1994),663-9 and R. T. Bartus et al., Neurological Res. 17 (1995), 249-58,demonstrated a neuroprotective action of calpain inhibitors in acuteneurodegenerative disorders or ischemia, such as occur after a stroke.After experimental brain trauma, calpain inhibitors improved thedeficits of memory performance and the neuromotoric disorders thatoccurred (K. E. Saatman et al. Proc.Natl.Acad.Sci. USA, 93, (1996),3428-3433). C. L. Edelstein et al., Proc.Natl.Acad.Sci. USA, 92 (1995),7662-6, observed a protective activity of calpain inhibitors in kidneysdamaged by hypoxia. Yoshida, Ken Ischi et al., Jap.Circ.J. 59(1) (1995),40-8, were able to demonstrate favorable effects of calpain inhibitorsafter cardial damage brought about by ischemia or reperfusion. Sincecalpain inhibitors inhibit the release of the β-AP4 protein, a potentialapplication as therapeutic agent for Alzheimer's disease has beensuggested (J. Higaki et al., Neuron, 14 (1995), 651-59). The release ofinterleukin-1α is also inhibited by calpain inhibitors (N. Watanabe etal., Cytokine 6(6) (1994), 597-601). It has furthermore beendemonstrated that calpain inhibitors exhibit cytotoxic effects in tumorcells (E. Shiba et al. 20th Meeting Int.Ass.Breast Cancer Res., SendaiJp, Sep. 25-28, 1994, Int.J.Oncol. 5(Suppl.), (1994), 381).

Further possible applications of calpain inhibitors are listed in K. K.Wang, Trends in Pharmacol.Sci., 15 (1994), 412-8.

Calpain inhibitors have already been described in the literature.However, they are predominantly either irreversible or peptidicinhibitors. Irreversible inhibitors are usually alkylating substances,which have the disadvantage that they react nonselectively in theorganism or that they are instable. For this reason, these inhibitorsoften exhibit undesirable side-effects, such as toxicity, and theirapplications are therefore limited, or they are not useful. Theirreversible inhibitors include, for example, the epoxides E 64 (E. B.McGowan et al., Biochem.Biophys.Res.Commun. 158 (1989), 432-5),α-haloketones (H. Angliker et al., J.Med.Chem. (1992), 216-20) anddisulfides (R. Matsueda et al., Chem.Lett. (1990), 191-194).

Many known reversible inhibitors of cysteine proteases, such as calpain,are peptidic aldehydes or ketones, in particular dipeptidic andtripeptidic aldehydes, such as, for example, Z-Val-Phe-H (MDL 28170) (S.Mehdi, Trends in Biol.Sci. 16 (1991), 150-3) and the compounds of EP520336. Under physiological conditions, peptidic aldehydes for exampleoften have the disadvantages that they are unstable owing to thereactivity present (J. A. Fehrentz and B. Castro, Synthesis, 19983[sic], 676-678), that they can be metabolized quickly, that they havelow water-solubility (important for intravenous application) or thatthey are slow to cross cell membranes, such as the blood-brain barrierand cellular membranes of neurons (calpain is an intracellular enzymeand any inhibitor has to penetrate into the cells). Thus, the best knownpeptidic inhibitors MDL 28170, AK 275 and AK 295 (Seung-Chuyl Hong etal., Stroke 25(3) (1994), 663-669; R. T. Bartus et al., J.Cerebral BloodFlow and Metabolism, 14 (1994), 537-544) have been studiedpharmacologically in animals, but effects were only observed when thesubstances were applied in a manner which is unconventional fortreatment, for example intracerebroventricularly or intra-arterially.The use of the known calpain-inhibiting peptidic aldehydes or ketones inthe treatment of disorders is therefore limited or not advantageous.

Furthermore, efforts are being made to develop reversible non-peptidiccalpain inhibitors. Thus, JP 8183759, JP 8183769, JP 8183771 and EP520336 describe aldehydes derived from dipeptides where saturatedcarbocyclic rings, for example cyclohexanes, or saturated heterocyclicrings, for example piperidines, were incorporated into these peptidicinhibitors replacing an amino acid, affording novel calpain inhibitors.

Furthermore, compounds have also been described which are derived fromthe structure

in particular compounds where aryl is a phenyl ring which may carrysimple substituents such as alkyl radicals (WO 95/09838; WO 93/14082;WO/12140; Synthesis 181 (1995); EP 363284; J 59206-344 and DT 2050679).However, as shown in Synthesis 181 (1995), compounds where aryl=phenylare only weak inhibitors of the enzyme calpain. It is not known whethersubstituents on this phenyl ring influence the inhibitory activity ofthe compounds.

It is an object of the present invention to provide non-peptidicbenzamidoaldehydes having an improved activity.

We have found that this object is achieved by benzamidoaldehydes of theformula I

and their tautomeric and isomeric forms and, if appropriate, theirphysiologically acceptable salts, where:

R¹ is phenyl, naphthalene, quinoline, isoquinoline, tetrahydroquinoline,tetrahydroisoquinoline, pyridine, pyrimidine, pyrazine, pyridazine,quinazoline, quinoxaline, thiophene, benzothiophene, benzofuran, furanor indole, where the aromatic and heteroaromatic rings may besubstituted by up to three radicals R⁴,

R² is hydrogen, chlorine, bromine, fluorine, phenyl with or withoutsubstitution by a C₁-C₄-hydrocarbon radical, —NHCO-C₁-C₄-alkyl, —NHCOPh,—NHCO-naphthyl, —NHSO₂-C₁₋₄-alkyl, CONH₂, COOH, —COO-C₁₋₄-alkyl,—O-C₁₋₄-alkyl, —CO—NH-C₁₋₄-alkyl, NO₂ or NH₂,

R³ is a C₁-C₆-hydrocarbon radical, which may also carry a cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indolyl, phenyl,pyridine or naphthyl ring, it being possible for the rings in turn to besubstituted by one or two radicals R⁴, or is an —SCH₃ radical,

R⁴ is C₁-C₄-alkyl, —O-C₁-C₄-alkyl, OH, Cl, F, Br, I, CF₃, NO₂, NH₂, CN,COOH, COO-C₁-C₄-alkyl, —NHCO-C₁-C₄-alkyl, —NHCOPh, —NHSO₂-C₁-C₄-alkyl,—NHSO₂-Ph, —(CH₂)_(n)—NR⁵R⁶ (R⁵ and R⁶ are identical or different andare each hydrogen, C₁₋₄-alkyl or together are a ring), —SO₂-C₁-C₄-alkylor —SO₂Ph,

X is a bond, —(CH₂)_(m)—, —(CH₂)_(m)—O—(CH₂)_(o)—,(CH₂)_(m)—S—(CH₂)_(o)—, —(CH₂)_(m)—SO—(CH₂)_(o)—,(CH₂)_(m)—SO₂—(CH₂)_(o)—, —CH═CH—, —C≡C—, —CO—CH═CH—, —CH═CH—CO-,—(CH₂)_(m)—CO—(CH₂)_(o)—, —(CH₂)_(m)—NR⁵CO—(CH₂)_(o)—,—(CH₂)_(m)—CONR⁵—(CH₂)_(o)—, —(CH₂)_(m)—NHSO₂—(CH₂)_(o)—,—(CH₂)_(m)—SO₂NH—(CH₂)_(o)—, —NH—CO—CH═CH—, —CH═CH—CO—NH— or phenyl withor without substitution by a radical R²,

n is the number 1 or 2,

m is the number 0, 1, 2, 3 or 4 and

o is the number 0, 1, 2, 3 or 4.

The compounds of the formula I can be employed as racemates or asenantiomerically pure compounds or as diastereomers. If enantiomericallypure compounds are desired, these can be obtained for example bycarrying out a classical racemate resolution of the compounds of theformula I or intermediates thereof using a suitable optically activebase or acid. Alternatively, the enantiomeric compounds can also beprepared by using commercially available compounds, for exampleoptically active amino acids.

The invention also provides compounds which are mesomeric or tautomericto compounds of the formula I, for example those compounds where theketo group of the formula I is present as the enol tautomer.

Some of the novel compounds I may contain a basic or acidic group. Inthese instances, compounds may exist in the form of theirphysiologically acceptable salts, which may be obtained by reacting thecompounds with a suitable acid or base.

Suitable acids are, for example, hydrochloric acid, citric acid,tartaric acid, lactic acid, phosphoric acid, acetic acid, formic acid,maleic acid, fumaric acid, malic acid, succinic acid, malonic acid,sulfuric acid, methanesulfonic acid and toluenesulfonic acid.

Suitable bases are, in particular, sodium hydroxide, potassiumhydroxide, ammonia and simple organic amines.

Preference is given to benzamidoaldehydes of the formula I where R² ishydrogen, C₁-C₄-alkyl, fluorine, chlorine or bromine, R³ is CH₂-phenyl,which may be substituted by R⁴, and R¹, X, n, m, and o are each asdefined above.

The benzamidoaldehydes I according to the invention can be prepared byvarious routes which are outlined in the synthesis scheme below.

The benzoic acid derivatives II are linked with suitable aminoalcoholsIII to give the corresponding benzamidoaldehydes IV. For this purpose,conventional peptide coupling methods are used, such as listed forexample in C. R. Larock, Comprehensive Organic Transformations, VCHPublisher, 1989, page 972f. or in Houben-Weyl, Methoden der organischenChemie, 4th edition, E5, Chapter V. Preference is given to using“activated” acid derivatives of II where the acid group COOH isconverted into a group COL. L is a leaving group, such as, for example,Cl, imidazole and N-hydroxybenzotriazole. This activated acid is thenreacted with amines to give the amides IV. The reaction is carried outin anhydrous inert solvents such as methylene chloride, tetrahydrofuranand dimethylformamide at from −20 to +25° C.

These alcohol derivatives IV may be oxidized to the aldehyde derivativesI according to the invention using various conventional oxidationreactions (see C. R. Larock, Comprehensive Organic Transformations, VCHPublisher, 1989, page 604 f.) such as, for example, Swern and Swern-likeoxidations (T. T. Tidwell, Synthesis 1990, 857-70), sodiumhypochlorite/TEMPO (S. L. Harbenson et al., see above) or theDess-Martin reagent (J.Org.Chem. 48 (1983), 4155). The reactions arepreferably carried out in inert aprotic solvents, such asdimethylformamide, tetrahydrofuran or methylene chloride, usingoxidizing agents, such as DMSO/pyridine x SO₃ or DMSO/oxalyl chloride,at from −50 to +25° C., depending on the method used (see literatureabove).

Alternatively, the benzoic acid II can be reacted with aminohydroxamicacid derivatives VI to give the benzamidoaldehydes I. For this purpose,the same reaction procedure as for the preparation of IV is used. Thehydroxam derivatives VI are obtainable from the protected amino acids Vby reaction with a hydroxylamine. As before, the amide preparationprocesses already described are employed here. The protecting group, forexample Boc, is cleaved in a conventional manner, for example usingtrifluoroacetic acid. The resultant benzamidohydroxamic acids VII can beconverted into the aldehydes I according to the invention by reduction,using, for example, lithium aluminum hydride as reducing agent at from−60 to 0° C. in inert solvents such as tetrahydrofuran or ether.

Similar to the last process, it is also possible to preparebenzamidocarboxylic acids or acid derivatives IX such as esters oramides which may also be converted into the aldehydes I according to theinvention by reduction. These processes are listed in R. C. Larock,Comprehensive Organic Transformations, VCH Publisher, (1989), page619-26.

The benzamidoaldehydes I are inhibitors of cysteine proteases such ascalpain I and II and cathepsin B and L and may thus serve to controldisorders which are linked to an increased enzyme activity of thecalpain enzymes and/or the cathepsin enzymes. The presentbenzamidoaldehydes I can therefore be used for the treatment ofneurodegenerative disorders which occur after ischemia, trauma,subarachnoidal bleeding and/or stroke, and/or of neurodegenerativedisorders such as multiple infarct dementia, Alzheimer's disease and/orHuntington's disease, and/or furthermore for the treatment of damage tothe heart after cardial ischemia, damage to the kidneys after renalischemia, damage to the skeletal muscles, muscular dystrophies, damagecaused by the proliferation of the smooth muscle cells, coronalvasospasms, cerebral vasospasms, cataracts of the eyes and/or ofrestenosis of the blood vessels after angioplasty. Additionally, thebenzamidoaldehydes I can be useful in the chemotherapy of tumors andtheir metastases, and/or in the treatment of disorders where increasedinterleukin-1 levels occur, such as inflammations and/or rheumaticdisorders.

The inhibitory activity of the benzamidoaldehydes I was determined usingenzyme tests which are customarily used in the literature, determiningas a measure of activity the concentration of the inhibitor where 50% ofthe enzyme activity is inhibited (=IC₅₀). In this manner, thebenzamidoaldehydes I were investigated for their inhibitory activity tocalpain I, calpain II and cathepsin B.

Cathepsin B Test

The inhibition of cathepsin B was determined similar to a method of S.Hasnain et al., J.Biol.Chem. 268 (1993), 235-40. 2 μl of an inhibitorsolution prepared from inhibitor and DMSO (final concentrations: 100 μmto 0.01 μm) were added to 88 μl of cathepsin B (cathepsin B from humanliver) (Calbiochem), diluted to 5 units in 500 μM buffer). Thisexperiment was preincubated for 60 minutes at room temperature (25° C.),and the reaction was then started by adding 10 μl of 10 mM Z-Arg-Arg-pNA(in a buffer containing 10% DMSO). The reaction was monitored for 30minutes at 405 nm in the microtiter plate reader. The IC₅₀-values werethen determined from the maximum slopes.

Calpain I and II Test

The inhibitory properties of calpain inhibitors were studied in a buffercontaining 50 mM of Tris-HCl, pH 7.5; 0.1 M of NaCl; 1 mM ofdithiotreithol; 0.11 mM of CaCl₂, using the fluorogenic calpainsubstrate Suc-Leu-Tyr-AMC (25 mM dissolved in DMSO, Bachem/Switzerland)(Sasaki et al. J. Biol. Chem. 1984, Vol. 259, 12489-12494). Humanμ-calpain is isolated from erythrocytes similarly to the methods ofCroall and DeMartino (BBA 1984, Vol. 788, 348-355) and Graybill et al.(Bioorg. & Med. Lett. 1995, Vol. 5, 387-392). After severalchromatographic steps (DEAE-Sepharose, Phenyl-Sepharose, Superdex 200and Blue-Sepharose), the enzyme is obtained in a purity of <[sic] 95%,according to SDS-PAGE, Western blot analysis and N-terminal sequencing.The fluorescence of the cleavage product 7-amino-4-methylcoumarin (AMC)is monitored in a Spex-Fluorolog fluorimeter at λ_(ex)=380 nm anλ_(em)=460 nm. Over a measured range of 60 min, the cleavage of thesubstrate is linear and the autocatalytic activity of calpain is lowwhen the experiments are carried out at 12° C. (see Chatterjee et al.1996, Bioorg. & Med. Chem. Lett., Vol 6, 1619-1622). Inhibitors andcalpain substrate are added to the experiment as DMSO solutions, and thefinal concentration of DMSO should not exceed 2%.

In a typical experiment, 10 μl of substrate (250 μm final) and then 10μl of μ-calpain (2 μg/ml final, i.e. 18 nM) are added to a 1 ml cuvettecontaining buffer. The calpain-mediated cleavage of the substrate ismeasured for 15 to 20 min. 10 μI of inhibitor (50 or 100 μM of DMSOsolution) are subsequently added and the inhibition of cleavage ismeasured for a further 40 min. K_(i) values are determined according tothe conventional equation for reversible inhibition, i.e.K:=1(v₀/v_(i))−1 [sic]; where I=inhibitor concentration, v₀=initial rateprior to addition of inhibitor; v_(i)=reaction rate at equilibrium.

For 2-phenyl-N-(3-phenylpropan-1-al-2-yl)benzamide (Example 30), a K_(i)of <0.5 μM was determined. This derivative is therefore significantlymore effective than the very closely relatedN-(1-3-phenylpropan-1-al-2-yl)benzamide (from M. R. Angelastro et al.,J. Med. Chem. 1990, 33, 11-13).

Calpain-mediated breakdown of tyrosine kinase pp60src in platelets

After the activation of platelets, tyrosine kinase pp60src was cleavedby calpain. This was thoroughly investigated by Oda et al. in J. Biol.Chem., 1993, Vol 268, 12603-12608. It was shown that the cleavage ofpp60src can be inhibited by calpeptin, an inhibitor of calpain. Inaccordance with this publication, the cellular efficacy of the novelsubstances was tested. Fresh human blood which had been treated withcitrate was centrifuged at 200 g for 15 min. The platelet-enrichedplasma was pooled and diluted 1:1 with platelet buffer (platelet buffer:68 mM of NaCl, 2.7 mM of KCl, 0.5 mM of MgCl₂×6H₂O, 0.24 mM ofNaH₂PO₄×H₂O, 12 mM of NaHCO₃, 5.6 mM of glucose, 1 mM of EDTA, pH 7.4).After one centrifugation and wash step using platelet buffer, theplatelets were adjusted to 10⁷ cells/ml. The isolation of the humanplatelets was carried out at room temperature.

In the experiment, isolated platelets (2×10⁶) were preincubated withdifferent concentrations of inhibitors (dissolved in DMSO) at 37° C. for5 min. The platelets were subsequently activated using 1 μM of ionophoreA23187 and 5 mM of CaCl₂. After 5 min of incubation, the platelets werebriefly centrifuged at 13000 rpm and the pellet was suspended in SDSsample buffer (SDS sample buffer: 20 mM of Tris-HCl, 5 mM of EDTA, 5 mMof EGTA, 1 mM of DTT, 0.5 mM of PMSF, 5 μg/ml of leupeptin, 10 μm ofpepstatin, 10% of glycerol and 1% of SDS). The proteins were separatedin a 12% gel and pp60src and its 52 kDa and 47 kDa cleavage productswere identified by Western blotting. The polyclonal rabbit antibodyanti-Cys-src (pp60^(c-src)) used was purchased from BiomolFeinchemikalien (Hamburg, FRG). This primary antibody was detected usingan HRP-coupled second antibody from goat (Boehringer Mannheim, FRG). TheWestern blotting was carried out according to known methods.

The cleavage of pp60src was quantified densitometrically usingnon-activated (control 1: no cleavage) and ionophore- andcalcium-treated platelets (control 2: corresponds to 100% cleavage) ascontrols. The ED₅₀ value corresponds to that concentration of inhibitorwhere the intensity of the color reaction of the 60 kDa band correspondsto the value intensity of control 1 plus control 2 divided by 2.

Glutamate-induced cell death in cortical neurons

The test was carried out in analogy to D. W. Choi, M.A. Maulucci-Geddeand A. R. Kriegstein, “Glutamate neurotoxicity in cortical cellculture”, J.Neurosci. 7 (1987), 357-368. Cortex hemispheres wereisolated from 15-day-old mouse embryos, and the individual cells wereobtained enzymatically (trypsin). These cells (glia and corticalneurons) were sown in 24 well plates. After three days (laminin-coatedplates) or seven days (ornithine-coated plates), the mitosis treatmentwas carried out using FDU (5-fluoro-2-deoxyuridine). 15 days after thecell preparation, cell death was induced by the addition of glutamate(15 minutes). After the glutamate has been removed, the calpaininhibitors are added. 24 hours later, the damage to the cells wasevaluated by determining the lactate dehydrogenase (LDH) in thesupernatant of the cell culture.

Calcium-mediated cell death in NT2 cells

In the human cell line NT2 (precursor cells, Stratagene GmbH), celldeath can be induced by calcium in the presence of the ionophore A23187.10⁵ cells/well were placed into microtiter plates 20 hours prior to theexperiment. After this time, the cells were incubated with variousconcentrations of inhibitors in the presence of 2.5 μmol of ionophoreand 5 μmol of calcium. After 5 hours, 0.05 ml of XTT (Cell ProliferationKit II, Boehringer Mannnheim) were added to the experiment.Approximately 17 hours later, the optical density was determined usingthe Easy Reader EAR 400 (SLT) according to the specifications of themanufacturer. The optical density at which half of the cells have diedis calculated from the two control experiments with cells withoutinhibitors which were incubated in the presence and absence ofionophore.

In a series of neurological disorders or mental disorders, an increasedglutamate activity is encountered leading to overexcitation or toxiceffects in the central nervous system (CNS).

Substances which inhibit the effects mediated by glutamate can thereforebe employed in the treatment of these diseases. Glutamate antagonists,and these include in particular NMDA antagonists or their modulators andAMPA antagonists, are suitable for therapeutic use as drugs forneurodegenerative disorders (Huntington's chorea and Parkinson'sdisease), neurotoxic disorders after hypoxia, anoxia and ischemia asencountered after strokes, or else as antiepileptics, antidepressantsand anxiolytics (cf. Arzneim. Forschung 1990, 40, 511-514; TIPS, 1990,11, 334-338 and Drugs of the Future 1989, 14 (11), 1059-1071).

Intracerebral administration of excitatory amino acids (=EAA) inducessuch a massive overexcitation that within a short period of time spasmsset in leading to the death of the animals. These symptoms can beinhibited by systemic—for example intraperitoneal—administration ofcentrally acting EAA antagonists. Since the excessive activation of EAAreceptors of the central nervous system plays an important role in thepathogenesis of various neurological disorders, an established EAAantagonism in vivo can be seen as an indication for the therapeuticsuitability of the substances against such CNS disorders. These include,inter alia, focal and global ischaemias, trauma, epilepsies and variousneurodegenerative disorders such as Huntington's chorea, Parkinson'sdisease, etc.

It has already been shown that calpain inhibitors in cell cultures alsohave protective activity against cell death triggered by EAA (H. Caueret al., Brain Research 1993, 607, 354-356; Yu Cheg and A. Y. Sun,Neurochem. Res. 1994, 19, 1557-1564). Surprisingly, the calpaininhibitors embraced by this application are active even against spasmstriggered by EAA (for example NMDA or AMPA) and therefore indicate atherapeutic use in the abovementioned CNS disorders.

The drug preparations according to the invention comprise atherapeutically active amount of the compounds I in addition to theconventional drug auxiliaries.

For local external applications, for example in powders, ointments orsprays, the active compounds may be present in customary concentrations.The active compounds are generally present in an amount of from 0.001 to1% by weight, preferably from 0.01 to 0.1% by weight.

When applied internally, the preparations are administered in singledoses containing from 0.1 to 100 mg per kg of body weight. Thepreparations may be administered daily in one or more doses depending onthe type and severity of the diseases.

Depending on the desired method of application, the drug preparationsaccording to the invention comprise the customary carriers and diluents,in addition to the active compound. Suitable for local externalapplication are pharmaceutical auxiliaries, such as ethanol,isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castoroil, polyacrylic acid, polyethylene glycol, polyethylene glycolstearate, ethoxylated fatty alcohols, paraffin oil, paraffin jelly andlanolin. Suitable for internal administration are for example lactose,propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone.

The preparations may further comprise antioxidants, such as tocopheroland butylated hydroxyanisol and butylated hydroxytoluene, additiveswhich improve the flavor, stabilizers, emulsifiers and lubricants.

The compounds which are present in the preparation in addition to theactive compound and the compounds used in the production of thepharmaceutical preparations are non-toxic and compatible with therespective active compound. The drug preparations are produced in aconventional manner, for example by mixing the active compound withother conventional carriers and diluents.

The drug preparations may be administered in various ways, for exampleorally, parenterally, such as intravenously by infusion, subcutaneously,intraperitoneally and topically. Preparation forms such as tablets,emulsions, solutions for infusions and injections, pastes, ointments,gels, creams, lotions, powders and sprays are possible.

EXAMPLES Example 1N-(Butan-1-al-2-yl)-2-((E-2-phenylethen-1-yl)amido)benzamide

a) 2-Amino-N-(butan-1-ol-2-yl)benzamide

10.0 g (61 mmol) of isatoic anhydride and 11 g (123.6 mmol) of2-amino-1-butanol in 200 ml of tetrahydrofuran were heated under refluxfor 8 hours. The tetrahydrofuran was then removed under reduced pressureand the resulting residue was distributed between 2M aqueous sodiumhydroxide solution and ethyl acetate. The ethyl acetate phase was driedand concentrated under reduced pressure. 10.5 g (82%) of the productwere obtained.

b) N-(Butan-1-ol-2-yl)-2-((E-2-phenylethen-1-yl)amido)benzamide

1 g (5 mmol) of the above intermediate 1a and 0.6 g (6 mmol) oftriethylamine were dissolved in 50 ml of tetrahydrofuran. At 0° C., 0.95g (5.7 mmol) of cinnamoyl chloride dissolved in a little tetrahydrofuranwas added dropwise in such a way that the temperature remained below 5°C. The mixture was stirred for 1 h. The reaction was then concentratedunder reduced pressure and the residue was distributed between 2Maqueous sodium hydroxide solution and ethyl acetate. The organic phasewas dried and concentrated under reduced pressure. This crude productwas boiled in ether and then filtered with suction. 1.1 g (56%) of theproduct were obtained.

c) N-(Butan-1-al-2-yl)-2-((E-2-phenylethen-1-yl)amido)benzamide

1.1 g (14 mmol) of dimethyl sulfoxide dissolved in 5 ml of methylenechloride were slowly added dropwise to 0.9 g (7 mmol) of oxalyl chloridein 25 ml of anhydrous methylene chloride at from −60 to −500° C. Themixture was stirred for 15 minutes. 2 g (6 mmol) of the intermediate 1bdissolved in 10 ml of methylene chloride were then added dropwise insuch a way that the temperature remained below −50° C. The mixture wasthen stirred for a further 30 min. 1.5 g (15 mmol) of triethylamine werethen added and the mixture was warmed to room temperature. The reactionmixture was washed with water and the organic phase was dried andconcentrated under reduced pressure. The residue was treated with etherand filtered with suction. 0.4 g (20%) of the product was obtained.

MS: m/e=336 (M⁺).

Example 2 N-(Butan-1-al-2-yl)-2-((2-naphthyl)amido)benzamide

a) N-(Butan-1-ol-2-yl)-2-((2-naphthyl)amido)benzamide

1 g (4.8 mmol) of the intermediate 1a and 0.95 g (5 mmol) of 2-naphthoylchloride were reacted by the method of procedure 1b. 1.05 g (62%) of theproduct were obtained.

b) N-(Butan-1-al-2-yl)-2-((2-naphthyl)amido)benzamide

0.9 g (2.5 mmol) of the intermediate 2a were oxidized by the method ofprocedure 1c using dimethyl sulfoxide/oxalyl chloride. Afterchromatographic purification (eluent: toluene/acetone=17/3), 78 mg (9%)of the product were obtained.

¹H-NMR(D₆-DMSO): δ=1.0 (3H); 1.6-2.0 (2H); 4.3 (1H); 7.2-8.8(11H); 9.0(1H); 9.7(1H) and 12.1(1H)ppm.

Example 3 N-(Butan-1-al-2-yl)-3-((2-naphthyl)amido)benzamide

a) N-(3-Ethoxycarbonylphenyl)-2-naphthoylamide

6.6 ml of triethylamine and, at 0-5° C., 9 g (47.5 mmol) of 2-naphthoylchloride dissolved in 50 ml of tetrahydrofuran were added successivelyto 7.5 g (45.5 mmol) of ethyl 3-aminobenzoate dissolved in 150 ml oftetrahydrofuran. The mixture was stirred for about 1 h. The mixture wasthen filtered and the residue was concentrated under reduced pressure.The resulting solid was treated with ether and filtered with suctiononce more. 9.3 g (64%) of the product were obtained.

b) 3-(2-Naphthylamido)benzoic acid

9.0 g (28 mmol) of the product 3a were dissolved in 100 ml oftetrahydrofuran and treated with 2.7 g (113 mmol) of lithium hydroxidedissolved in 50 ml of water. The mixture was stirred at room temperatureuntil the reaction had ended (about 6 h). The tetrahydrofuran was thenremoved under reduced pressure and the resulting aqueous phase wasacidified using 2M hydrochloric acid. The precipitate was filtered offwith suction. 7.8 g (95%) of the product were obtained.

c) N-(Butan-1-ol-2-yl)-3-((2-naphthyl)amido)benzamide

At 0° C., 0.8 g (7.7 mmol) of ethyl chloroformate dissolved in a littletetrahydrofuran was added dropwise to 2 g (6.9 mmol) of the intermediate3b and 0.8 g (7.9 mmol) of triethylamine dissolved in 50 ml of anhydroustetrahydrofuran. At −20 to −10° C., 0.6 g (6.7 mmol) of 2-aminobutanolwere then added dropwise. The mixture was stirred at room temperaturefor 16 h. The tetrahydrofuran was then removed under reduced pressureand the residue was distributed between water and ethyl acetate. Theorganic phase was dried and concentrated under reduced pressure. Theproduct was boiled with ether and filtered with suction. 1.5 g (58%) ofthe product were obtained.

d) N-(Butan-1-al-2-yl)-3-(2-naphthylamido)benzamide

1.3 g (3.5 mmol) of the intermediate 3c were oxidized by the method ofthe procedure 1c using dimethyl sulfoxide/oxalyl chloride. After achromatographic purification (eluent: toluene/acetone=1/1), 0.24 g (18%)of the product was obtained.

¹H-NMR(D₆-DMSO): δ=1.0(3H); 1.6-2.0 (2H); 4.2(1H), 7.3-8.8 (10H);8.9(1H), 9.4(1H) and 10.5(1H)ppm.

Example 4 (S)-N-(3-Phenylpropan-1-al-2-yl)-2-(3-pyridyl)amidobenzamide

a) (S)-2-Amino-N-(3-phenylpropan-1-ol-2yl)benzamide

The product was prepared by the method of procedure 1a from 5 g(S)-(-)-2-amino-3-phenyl-1-propanol and isatoic anhydride. 3.6 g of theproduct were obtained.

b) (S)-N-(3-Phenylpropan-1-ol-2-yl)-2-(3-pyridyl)amidobenzamide

1.0 g (3.7 mmol) of the intermediate 4a was dissolved in 25 ml ofpyridine and, at 0° C., mixed a little at a time with 0.7 g (3.9 mmol)of nicotinoyl chloride hydrochloride. The reaction mixture was stirredfor a number of hours (DC control). The mixture was then concentratedunder reduced pressure. The resulting crude product (about 2 g) was usedas such for further reactions.

c) (S)-N-(3-Phenylpropan-1-al-2-yl)-2-(3-pyridyl)amidobenzamide

2 g of the intermediate 4b were oxidized by the method of procedure 1cusing dimethyl sulfoxide/oxalyl chloride. After chromatographicpurification (eluent: toluene/acetone=1/1), 0.17 g of the product wasobtained.

MS: m/e=373 (M⁺).

Example 5 (S)-N-(3-Phenylpropan-1-al-2-yl)-2-(2-naphthyl)amidobenzamide

a) (S)-N-(3-Phenylpropan-1-ol-2-yl)-2-(2-naphthyl)amidobenzamide

1.5 g (5.6 mmol) of the intermediate 4a were reacted with 1.2 g (6.3mmol) of naphthoyl chloride by the method of the procedure 4b. 1.4 g(58%) of the product were obtained.

b) (S)-N-(3-Phenylpropan-1-al-2-yl)-2-(2-naphthylamido)benzamide

1.2 g (4.7 mmol) of the intermediate 5a were oxidized by the method ofprocedure 1c using oxalyl chloride/dimethyl sulfoxide. 0.5 g (42%) ofthe product was obtained.

MS: m/e=422(M⁺).

Example 6 (S)-N-(3-Phenylpropan-1-al-2-yl)-3-(2-naphthyl)amidobenzamide

a) (S)-N-(3-Phenylpropan-1-ol-2-yl)-3-(2-naphthylamido)benzamide

2 g (6.8 mmol) of the intermediate 3b were reacted with(S)-2-amino-3-pheyl-1-propanol [sic] by the method of procedure 3c. 1 g(34%) of the product was obtained.

b) (S)-N-(3-Phenylpropan-1-al-2-yl)-3-(2-naphthyl)amidobenzamide

0.9 g (2.1 mmol) of the intermediate 6a was oxidized with dimethylsulfoxide/oxalyl chloride by the method of procedure 1c. Afterchromatographic purification (eluent: toluene/acetone=3/1), 0.2 g (22%)of the product was obtained.

MS: m/e=422(M⁺).

Example 7(S)-2-(2-Phenyl-1-ethyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-2-(2-Phenyl-1-ethyl) amido-N-(3-phenylpropan-1-al-2-yl)benzamide

0.3 g (2.2 mmol) of N-hydroxybenzotriazole (HOBT) and, a little at atime, 1.3 g (6.6 mmol) of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide(EDC) were added successively to 1.5 [lacuna] (6.6 mmol) of2-(2-phenyl-1-ethyl)benzoic acid, 1.0 g (6.6 mmol) of(S)-2-amino-3-phenylpropan-1-ol and 1.4 ml (9.9 mmol) of triethylaminein 50 ml of methylene chloride. The mixture was stirred at roomtemperature for 16 h. The reaction mixture was then diluted with a largevolume of ethyl acetate and washed successively twice with 2Mhydrochloric acid, twice with 2M aqueous sodium hydroxide solution andthree times with water. The organic phase was dried and concentratedunder reduced pressure. The residue was precipitated from methylenechloride/petroleum ether. 1.85 g (79%) of the product were obtained.

b) (S)-2-(2-Phenyl-1-ethyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

1.6 g (4.5 mmol) of the intermediate 7a were oxidized with dimethylsulfoxide/oxalyl chloride by the method of procedure 1c. 0.7 g (46%) ofthe product was obtained.

¹H-NMR (CDCl₃): δ=2.8-3.4(6H); 4.9(1H); 6.1(1H); 7.0-7.6(14H) and9.8(1H)ppm

Example 8 (S)-3-Benzoyl-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-3-Benzoyl-N-(3-phenylpropan-1-ol-2-yl)benzamide

2 g (8.8 mmol) of 3-benzoylbenzoic acid were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 2.5 g(79%) of the product were obtained.

b) (S)-3-Benzoyl-N-(3-phenylpropan-1-al-2-yl)benzamide

2 g (5.6 mmol) of the intermediate 8a were oxidized by the method ofprocedure 1c. After chromatographic purification (eluent: methylenechloride/methanol=10:1), 1.2 g (61%) of the product were obtained.

MS: m/e=357(M⁺).

Example 9 (S)-2-Benzoyl-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-2-Benzoyl-N-(3-phenylpropan-1-ol-2-yl)benzamide

2-Benzoylbenzoic acid was reacted with (S)-2-amino-3-phenyl-1-propanolby the method of procedure 3c. 2.6 g (86%) of the product were obtained.

b) (S)-2-Benzoyl-N-(3-phenylpropan-1-al-2-yl)benzamide

2.4 g (6.7 mmol) of the intermediate 9a were oxidized with dimethylsulfoxide/oxalyl chloride by the method of procedure 1c. Afterchromatographic purification (eluent=toluene/ethyl acetate=20/1), 0.5 g(21%) [lacuna] was obtained.

MS: m/e=357 (M⁺).

Example 10 (S)-3-(1-Naphthyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) 3-(1-Naphthylamido)benzoic acid

At 0° C., 7.3 g (38 mmol) of 1-naphthoyl chloride dissolved in 25 ml oftetrahydrofuran were added dropwise to 5 g (36.5 mmol) of 3-aminobenzoicacid and 10 ml (73 mmol) of triethylamine in 100 ml of anhydroustetrahydrofuran. The mixture was stirred at 0° C. for 1 h. The mixturewas then concentrated under reduced pressure and the residue wasdistributed between ethyl acetate and 2M hydrochloric acid whereupon theproduct crystallized out. 7.8 g (74%) of the product were obtained.

b) (S)-3-(1-Naphthyl)amido-N-(3-phenylpropan-1-ol-2-yl)benzamide

1 g (3.4 mmol) of the intermediate 10a was reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a, affording1.1 g (76%) of the product.

c) (S)-3-(1-Naphthyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

1.0 g (2.3 mmol) of the intermediate 10b was oxidized with dimethylsulfoxide/oxalyl chloride by the method of procedure 1c. 0.35 g (35%) ofthe product was obtained.

¹H-NMR(CDCl₃): δ=3.1(2H); 4.6(1H); 7.0-8.4(18H) and 9.6(1H)ppm.

Example 11 (S)-4-(2-Naphthyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) 4-(2-Naphthyl)amidobenzoic acid

5 g (36.5 mmol) of 4-aminobenzoic acid were reacted with 2-naphthoylchloride by the method of procedure 10a, affording 6.6 g (62%) of theproduct.

b) (S)-4-(2-Naphthyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

1 g (3.4 mmol) of the intermediate 11a was reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a. 0.9 g(62%) of the product was obtained.

c) (S)-4-(2-Naphthyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

0.8 g (1.9 mmol) of the intermediate 11b was oxidized with dimethylsulfoxide/oxalyl chloride by a method of procedure 1c. Afterchromatographic purification (eluent: methylene chloride/methanol=15/1),0.4 g (53%) of the product was obtained.

¹H-NMR(D₆-DMSO): [lacuna]=2.9(1H); 3.3(1H); 4.5(1H); 7.0-8.3 (14H);8.6(1H); 8.8(1H); 9.6(1H) and 10.6(1H)ppm.

Example 12(S)-2-(2-Naphthyl)sulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-2-(2-Naphthyl)sulfonamido-N-(3-phenylpropan-1-ol-2-yl)benzamide

1.5 g (5.6 mmol) of (S)-2-amino-N-(3-phenylpropan-1-ol-2-yl)benzamide(intermediate 4a) were reacted with 2-naphthylsulfonyl chloride by themethod of procedure 4b. 0.67 g of the product was obtained.

b) (S)-2-(2-Naphthyl)sulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

0.6 g (1.3 mmol) of the intermediate 12a was oxidized with dimethylsulfoxide/oxalyl chloride by the method of procedure 1c. Afterchromatographic purification (eluent: toluene/acetone=1/2), 0.4 g of theproduct was obtained.

MS: m/e=458(M⁺).

Example 13 (S)-2-Benzyl-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-2-Benzyl-N-(3-phenylpropan-1-ol-2-yl)benzamide

At 0° C., 2.1 g (9.2 mmol) of 2-benzylbenzoyl chloride dissolved in alittle methylene chloride were added dropwise to 1.3 g (8.6 mmol) of(S)-2-amino-3-phenylpropan-1-ol in 35 ml of methylene chloride and 20 mlof 2M aqueous sodium hydroxide solution. The mixture was stirred forabout 30 min. The organic phase was separated off, dried andconcentrated under reduced pressure. 2.7 g (91%) of the product wereobtained.

b) (S)-2-Benzyl-N-(3-phenylpropan-1-al-2-yl)benzamide

2 g (5.8 mmol) of the intermediate 13a were oxidized with dimethylsulfoxide/oxalyl chloride by the method of procedure 1c. 1.5 g (75%) ofthe product were obtained.

¹H-NMR(D₆-DMSO): δ=2.8(1H); 3.3(1H); 4.0(2H); 4.5(1H); 7.0-7.5(1H);8.8(1H) and 9.5(1H)ppm.

Example 14(S)-6-Methyl-2-(2-naphthyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-2-Aminomethyl-N-(3-phenylpropan-1-al-2-yl)benzamide

5 g (28.2 mmol) of 5-methylisatoic anhydride and 4.3 g (28.5 mmol) of(S)-2-amino-3-phenyl-1-propanol in 150 ml of tetrahydrofuran were heatedat reflux for about 8 h. The mixture was then concentrated under reducedpressure and the residue was distributed between ethyl acetate and 2Maqueous sodium hydroxide solution. The organic phase was dried and onceagain concentrated under reduced pressure. This residue was then treatedwith ether, affording 3.2 g (39%) of the product.

b)(S)-6-Methyl-2-(2-naphthyl)amido-N-(3-phenylpropan-1-ol-2-yl)benzamide

2 g (7 mmol) of the intermediate 14a were reacted with 2-naphthoylchloride by the method of procedure 10a. 2.7 g (77%) of the product wereobtained.

(S)-6-Methyl-2-(2-naphthyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

2 g (4.6 mmol) of the intermediate 14b were oxidized with dimethylsulfoxide/trifluoroacetic anhydride by the method of procedure 1c. Afterchromatographic purification (eluent: tetrahydrofuran/toluene/ethylacetate=5/10/5), 1 g (50%) of the product was obtained.

MS: m/e=436 (M⁺).

Example 15 (S)-2-Phenyloxymethyl-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-2-Phenyloxymethyl-N-(3-phenylpropan-1-ol-2-yl)benzamide

2 g (8.8 mmol) of 2-phenoxymethylbenzoic acid were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a. 2.7 g(84%) of the product were obtained.

b) (S)-2-Phenyloxymethyl-N-(3-phenylpropan-1-al-2-yl)benzamide

2 g (5.5 mmol) of the intermediate 15a were oxidized with dimethylsulfoxide/trifluoroacetic anhydride by the method of procedure 3c. Afterchromatographic purification (eluent: toluene/ethyl acetate=10/1), 1.6 g(79%) of the product were obtained.

MS: m/e=359(M⁺).

Example 16 (S)-4-Benzoyl-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-4-Benzoyl-N-(3-phenylpropan-1-ol-2-yl)benzamide

3 g (13 mmol) of benzophenone-4-carboxylic acid were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 3.2 g(67%) of the product were obtained.

b) (S)-4-Benzoyl-N-(3-phenylpropan-1-al-2-yl)benzamide

2.4 g (6.7 mmol) of the intermediate 16a were oxidized with dimethylsulfoxide/trifluroacetic [sic] anhydride by the method of procedure 3c.After chromatographic purification (eluent:toluene/tetrahydrofuran=10/1), 0.3 g (13%) of the product was obtained.

MS: m/e=357(M⁺).

Example 17(S)-2-(E-2-Phenyl-1-ethenyl)-N-(3-phenylpropan-1-al-2-yl)benzamide

a) Ethyl 2-(E-2-phenyl-1-ethenyl)benzoate

8.9 g (38.9 mmol) of ethyl 2-bromobenzoate, 5.1 g (49.4 mmol) ofstyrene, 0.18 g (0.8 mmol) of palladium diacetate, 0.48 g (1.6 mmol) oftri-o-tolylphosphine and 5 g (49.1 mmol) of triethylamine were reactedin 90 ml of anhydrous acetonitrile at 100° C. for 23 h. The mixture wasthen filtered and the filtrate was diluted with ethyl acetate, washedwith water, dried and concentrated under reduced pressure. 10.2 g (100%)of the product were obtained.

b) 2-(E-2-Phenyl-1-ethenyl)benzoic acid

10 g (39.5 mmol) of the intermediate 17a, together with 3.2 g (79 mmol)of sodium hydroxide in 100 ml of water, were heated under reflux for 10h. The mixture was then diluted with water and washed with ether. Theaqueous phase was acidified with 1M hydrochloric acid whereupon theproduct precipitated. 6.2 g (70%) of the product were obtained.

c) (S)-2-(E-2-Phenyl-1-ethenyl)-N-(3-phenylpropan-1-ol-2-yl)benzamide

1.0 g (4.5 mmol) of the intermediate 17b and 0.67 g (4.5 mmol) of(S)-2-amino-3-phenyl-1-propanol were reacted by the method of procedure7a. 1.5 g (94%) of the product were obtained.

d) (S)-2-(E-2-Phenyl-1-ethenyl)-N-(3-phenylpropan-1-al-2-yl)benzamide

1.5 g (4.2 mmol) of the intermediate 17c were oxidized with dimethylsulfoxide/trifluoroacetic anhydride by the method of procedure 1c. Afterchromatographic purification (eluent: methylene chloride/methanol=20/1),0.85 g (58%) of the product were obtained.

MS: m/e=355 (M⁺).

Example 18 (S)-2-Phenylethynyl-N-(3-phenylpropan-1-al-2-yl)benzamide

a) Ethyl 2-phenylethynylbenzoate

11.5 g (50.2 mmol) of ethyl 2-bromobenzoate, 6.15 g (60.2 mmol) ofphenylacetylene, 0.16 g of bis(triphenylphosphino)palladium(II)dichloride and 0.08 g of copper(I) iodide in 10 ml of anhydroustriethylamine were heated under reflux for 6 hours. The reaction mixturewas then diluted with ether, washed with water, dried and concentratedunder reduced pressure. The residue was purified chromatographically(eluent: n-heptane/ethyl acetate=10/1), affording 11.3 [lacuna] (91%) ofthe product.

2-Phenylethynylbenzoic acid

11 g (44 mmol) of the intermediate 18a in 100 ml of tetrahydrofuran wereadmixed with 4.9 g (88 mmol) of potassium hydroxide dissolved in 200 mlof water, and the mixture was heated under reflux for 8 h. Thetetrahydrofuran was then removed under reduced pressure and the aqueousphase that remained was washed with ether. The aqueous phase wasacidified with dilute hydrochloric acid and extracted with ethylacetate. After drying and concentrating, 9.5 g (98%) of the product wereobtained.

c) (S)-2-Phenylethynyl-N-(3-phenylpropan-1-ol-2-yl)benzamide

2 g ([lacuna] mmol) of the intermediate 18b were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a, affording1.2 g (38%) of the product after chromatographic purification (eluent:toluene/acetone=10/1).

d) (S)-2-Phenylethynyl-N-(3-phenylpropan-1-al-2-yl)benzamide

1.0 g (2.8 mmol) of the intermediate 18c was oxidized with dimethylsulfoxide/trifluoroacetic anhydride by the method of procedure 1c. Afterchromotographic purification (eluent: methylene chloride/ethylacetate=10/1), 0.14 g (14%) of the product was obtained.

MS: m/e=353(M⁺).

Example 19(S)-2-(2-Naphthylmethyloxy)-N-(3-phenylpropan-1-al-2-yl)benzamide

a) Methyl 2-(2-naphthylmethyloxy)benzoate

3.9 g (35 mmol) of potassium tert-butoxide were added a little at a timeto 5 g (33 mmol) of methyl salicylate in 200 ml of dimethylformamide).After about 15 min, 7.3 g (33 mmol) of 2-(bromomethyl)naphthalene wereadded and the reaction mixture was heated to 100° C. for about 3 h. Thereaction mixture was then poured into ice-water and the product wasextracted with ethyl acetate. The organic phase was dried andconcentrated under reduced pressure. 9.15 g (95%) of the product wereobtained.

b) 2-(2-Naphthylmethyloxy)benzoic acid

8 g (3.4 mmol) of the intermediate 19a were hydrolyzed by the method ofprocedure 3b. 7 g (64%) of the product were obtained.

c) (S)-2-(2-Naphthylmethyloxy)-N-(3-phenylpropan-1-ol-2-yl)benzamide

2.45 g (8.8 mmol) of the intermediate 19b were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a, affording1.1 g (28%) of the product after chromatographic purification (eluent:toluene/tetrahydrofuran/triethylamine=20/10/1).

d) (S)-2-(2-Naphthylmethyloxy)-N-(3-phenylpropan-1-al-2-yl)benzamide

1.5 g (3.6 mmol) of the intermediate 19c were oxidized with dimethylsulfoxide/trifluoroacetic anhydride by the method of procedure 1c. 1.3 g(87%) of the product were obtained.

¹H-NMR(D₆-DMSO): δ=2.9(1H); 3.2(1H); 4.6(1H); 5.3(2H); 6.9-8.1(16H);8.6(1H) and 9.6(1H)ppm.

Example 20(S)-4-(2-Naphthylmethyloxy)-N-(3-phenylpropan-1-al-2-yl)benzamide

a) Methyl 4-(2-naphthylmethyloxy)benzoate

3.9 g (35 mmol) of potassium tert-butoxide were added a little at a timeto 5 g (33 mmol) of methyl hydroxybenzoate in 200 ml ofdimethylformamide. After about 15 min, a further 7.3 g (33 mmol) of2-(bromomethyl)naphthalene were added and the reaction mixture washeated to 100° C. for about 3 h. The reaction mixture was then pouredinto ice-water and the product was extracted with ethyl acetate. Theorganic phase was dried and concentrated under reduced pressure. 8.4 g(88%) of the product were obtained.

b) 4-(2-Naphthylmethyloxy)benzoic acid

8 g (3.4 mmol) of the intermediate 20a were hydrolyzed by the method ofprocedure 3b. 2.3 g (30%) of the product were obtained.

c) (S)-4-(2-Naphthylmethyloxy)-N-(3-phenylpropan-1-ol-2-yl)benzamide

2.3 g (8.3 mmol) of the intermediate 20b were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a, affording2.95 g (87%) of the product.

d) (S)-2-(2-Naphthylmethyloxy)-N-(3-phenylpropan-1-al-2-yl)benzamide

1.5 g (3.6 mmol) of the intermediate 20c were oxidized with dimethylsulfoxide/trifluoroacetic anhydride by the method of procedure 1c. 0.96g (64%) of the product was obtained.

¹H-NMR(D₆-DMSO): δ=2.9(1H); 3.2(1H); 4.3(1H); 5.3(2H); 7.0-8.0(16H);8.6(1H) and 9.5(1H)ppm.

Example 21(S)-4-(2-Naphthylamido)methyl-N-(3-phenylpropan-1-al-2-yl)benzamide

a) 4-(2-Naphthylamido)methylbenzoic acid

2.5 g (15.5 mmol) of 4-aminomethylbenzoic acid and 2-naphthoyl chloridewere reacted by the method of procedure 4b, affording 2.1 g (42%) of theproduct.

b) (S)-4-(2-Naphthylamido)methyl-N-(3-phenylpropan-1-ol-2-yl)benzamide

1.4 g (4.6 mmol) of the intermediate 21a were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c, affording1.1 g (55%) of the product.

c) (S)-4-(2-Naphthylamido)methyl-N-(3-phenylpropan-1-al-2-yl)benzamide

0.8 g (1.8 mmol) of the intermediate 21b and 1.0 ml (7.3 mmol) oftriethylamine were dissolved in 10 ml of anhydrous dimethyl sulfoxideand treated with 1.16 g (7.3 mmol) of sulfur trioxide-pyridine complexdissolved in 10 ml of dimethyl sulfoxide. The mixture was stirred atroom temperature for 16 h. The mixture was then poured into water andthe precipitate was filtered off with suction. 0.65 g (82%) of theproduct was obtained.

¹H-NMR(D₆-DMSO): δ=2.9(1H); 3.3(1H); 4.5(1H), 4.6(2H); 7.1-8.1 (15H);8.5(1H); 8.8(1H); 9.2(1H) and 9.6 (1H)ppm.

Example 22(S)-3-(2-Naphthyl)sulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) 3-(2-Naphthylsulfonamido)benzoic acid

5 g (35.5 mmol) of 3-aminobenzoic acid and 8.3 g (36.5 mmol) of2-naphthylsulfonyl chloride were reacted by the method of procedure 4b,affording 10.5 g (89%) of the product.

b) (S)-3-(2-Naphthyl)sulfonamido-N-(3-phenylpropan-1-ol-2-yl)benzamide

1 g (3.1 mmol) of the intermediate 22a was reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a, affording1.2 g (86%) of the product.

c) (S)-3-(2-Naphthyl)sulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

1.0 g (2.2 mmol) of the intermediate 22b was oxidized with dimeth [sic]sulfoxide/oxalyl chloride by the method of procedure 1c.

MS: m/e=458(M⁺).

Example 23(S)-2-(2-Naphthyl)amido-4-nitro-N-(3-phenylpropan-1-al-2-yl)benzamide

a) 2-(2-Naphthylamido)-4-nitro-benzoic acid

20 g (0.11 mmol) of 2-amino-4-nitrobenzoic acid were reacted with2-naphthylbenzoyl chloride by the method of procedure 4b, affording 22.3g (61%) of the product.

b) (S)-2-(2-Naphthyl)amido-4-nitro-N-(3-phenylpropan-1-ol-2-yl)benzamide

2 g (59.5 mmol) of the intermediate 23a were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c, affording2.5 g (90%) of the product.

c) (S)-2-(2-Naphthyl)amido-4-nitro-N-(3-phenylpropan-1-al-2-yl)benzamide

1.1 g (2.3 mmol) of the intermediate 23b were oxidized by the method ofprocedure 21c, affording 1.0 g (92%) of the product.

MS: m/e=467 (M⁺).

Example 24(S)-4-(8-Quinolinylsulfonamido)-N-(3-phenylpropan-1-al-2-yl)benzamide

a) Ethyl 4-(8-quinolinesulfonylamido)benzoate

2 g (12 mmol) of ethyl 4-aminobenzoate were reacted with8-quinolinesulfonyl chloride by the method of procedure 10a, affording3.5 g (82%) of the product.

b) 4-(8-Quinolinesulfonylamido)benzoic acid

3.3 g (9.3 mmol) of the intermediate 24a and 1.6 g (27.8 mmol) ofpotassium hydroxide in 100 ml of water were heated to 95° C. for 45 min.The mixture was then neutralized with acetic acid and the resultingprecipitate was filtered off with suction. 1.7 g (57%) of the productwere obtained.

c) (S)-4-(8-Quinolinylsulfonamido)-N-(3-phenylpropan-1-ol-2-yl)benzamide

1.5 g (4.6 mmol) of the intermediate 24b were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a, affording1.2 g (58%) of the product.

d) (S)-4-(8-Quinolinylsulfonamido)-N-(3-phenylpropan-1-al-2-yl)benzamide

1 g (2.2 mmol) of the intermediate was oxidized by the method ofprocedure 21c, affording 0.8 g of the product.

¹H-NMR (D₆-DMSO): [lacuna]=2.8(1H); 3.2(1H); 4.3(1H); 7.0-7.3(7H);7.5(2H); 7.7(3H); 8.2(1H); 8.4(2H); 8.7(1H); 9.1(1H); 9.5(1H) and10.6(1H)ppm.

Example 25(S)-4-(2-Naphthyl)thiomethyl-N-(3-phenylpropan-1-al-2-yl)benzamide

a) Methyl 4-(2-naphthylthiomethyl)benzoate

16.8 g (0.1 mol) of thionaphth-2-ole and 21.3 g (0.21 mol) oftriethylamine were dissolved in 300 ml of tetrahydrofuran. At 0° C., asolution of 24 g (0.1 mol) of methyl 4-(bromomethyl)benzoate in 100 mlof tetrahydrofuran was added dropwise. The mixture was stirred for 2 hand then filtered, and the filtrate was concentrated under reducedpressure. The residue was recrystallized from n-heptane, affording 27.2g (84%) of the product.

b) 4-(2-Naphthylthiomethyl)benzoic acid

25.9 g (42 mmol) of the intermediate 25a were hydrolyzed with 2Methanolic sodium hydroxide solution by the method of procedure 31b. 11.9g (96%) of the product were obtained.

c) (S)-4-(2-Naphthyl)thiomethyl-N-(3-phenylpropan-1-al-2-yl)benzamide

5.7 g (37 mmol) of (S)-2-amino-3-phenyl-1-propanol were reacted with 11g (37 mmol) of the intermediate 25b by the method of procedure 7a. 9.5 g(60%) of the product were obtained.

d) (S)-4-(2-Naphthyl)thiomethyl-N-(3-phenylpropan-1-al-2-yl)benzamide

5 g (2.3 mmol) of the intermediate 25c were oxidized by the method ofprocedure 21c. 0.9 g (18%) of the product was obtained.

¹H-NMR(D₆-DMSO): δ=2.9(1H); 3.3(1H); 4.4(2H); 4.5(1H); 7.0-7.9(16H);9.8(1H) and 10.5(1H)ppm.

Example 26 (S)-2-Phenoxy-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-2-Phenoxy-N-(3-phenylpropan-1-ol-2-yl)benzamide

7.3 g (48 mmol) of (S)-2-amino-3-phenyl-1-propanol were reacted with10.7 g (50 mmol) of 2-phenoxybenzoic acid by the method of procedure 3c.17.3 g (100%) of the product were obtained.

(S)-2-Phenoxy-N-(3-phenylpropan-1-al-2-yl)benzamide

16.1 g (46 mmol) of the intermediate 26a were oxidized by the method ofprocedure 21c. 10.3 g (64%) of the product were obtained.

¹H-NMR(D₆-DMSO): δ=2.9(1H); 3.2(1H); 4.5(1H); 6.7-7.7(14H); 8.4(1H) and9.4(1H)ppm.

Example 27(S)-4-(2-Naphthylmethyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) Ethyl 4-(2-Naphthylmethyl)amidobenzoate

10 g (53 mmol) of naphthyl acetic acid in 150 ml of anhydroustetrahydrofuran were admixed with 9 g (56 mmol) of carbonyldiimidazole,and the mixture was heated under reflux for 1 h. 8.9 g (3 mmol) of ethyl4-aminobenzoate were then added and the mixture was heated under refluxfor a further 3 h. The mixture was then concentrated under reducedpressure. The residue was treated with 600 ml of water whereupon theproduct precipitated. 16.6 g (92%) of the product were obtained.

b) 4-(2-Naphthylmethyl)amidobenzoic acid

15.2 g (46 mmol) of the intermediate 27a were hydrolyzed with lithiumhydroxide by the method of procedure 3b. 13.7 g (98%) of the productwere obtained.

c) (S)-4-(2-Naphthylmethyl)amido-N-(3-phenylpropan-1-ol-2-yl)benzamide

10.3 g (34 mmol) of the intermediate 27b were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 27a. 7.9 g(53%) of the product were obtained.

d) (S)-4-(2-Naphthylmethyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

7.4 g (17 mmol) of the intermediate 27c were oxidized by the method ofprocedure 21c. 2.1 g (28%) of the product were obtained.

¹H-NMR (D₆-DMSO): δ=MS(ESI): m/e=436(M⁺).

Example 284-(Naphth-2-ylsulfoxymethyl)-N-((S)-3-phenylpropan-1-al-2-yl)benzamide

a) Methyl 4-(naphth-2-ylsulfoxymethyl)benzoate

At 0° C., 25.8 g (42 mmol) of oxone dissolved in 300 ml of water wereadded dropwise to 13 g (42 mmol) of the intermediate 25a in 850 ml ofmethanol. The mixture was stirred for about 1 h. About 11 of water wasthen added and the precipitated product was filtered off with suction.13.2 g (92%) of the product were obtained.

b) 4-(Naphth-2-ylsulfoxymethyl)benzoic acid

12.7 g (39 mmol) of the intermediate 28a were hydrolyzed with sodiumhydroxide solution in ethanol/water by the method of procedure 31b. 11.5g (94%) of the product were obtained.

c) 4-(2-Naphthyl)sulfoxymethyl-N-((S)-3-phenylpropan-1-ol-2-yl)benzamide

10.2 g (31 mmol) of the intermediate 28b were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a. 8.7 g(61%) of the product were obtained.

d) 4-(2-Naphthyl)sulfoxymethyl-N-((S)-3-phenylpropan-1-al-2-yl)benzamide

7.46 g (17 mmol) of the intermediate 27c were oxidized by the method ofprocedure 21c. 4.2 g (55%) of the product were obtained.

¹H-NMR(D₆-DMSO): δ=2.9(1H); 3.2(1H); 4.2(1H); 4.5(2H); 7.0-8.1(16H);8.8(1H) and 9.5(1H)ppm.

Example 29(S)-4-(Naphth-2-yl)sulfonylmethyl-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-4-(Naphth-2-yl)sulfonylmethyl-N-(phenylpropan-1-ol-2-yl)benzamide

With cooling, 5.1 g of 55% strength (16.1 mmol) 3-chloroperbenzoic acidwere added a little at a time to 3.45 g (8.1 mmol) of(S)-4-naphthyl-2-thiomethyl-N-(3-phenylpropan-1-al-2-yl)benzamide(intermediate 25c) in 500 ml of methylene chloride. The mixture wasstirred at room temperature for 16 [lacuna]. The reaction solution wasthen washed three times with 20% strength aqueous sodium sulfitesolution. The organic phase was dried and concentrated under reducedpressure. 0.5 g (14%) of the product was obtained.

b)(S)-4-(Naphth-2-yl)sulfonylmethyl-N-(3-phenylpropan-1-al-2-yl)benzamide

0.4 g (0.9 mmol) of the intermediate 29a was oxidized by the method ofprocedure 21c. 0.36 g (88%) of the product was obtained.

¹H-NMR(D₆-DMSO): δ=2.9(1H); 3.3(1H); 4.5(1H); 4.9(2H); 7.0-7.3(6H);7.5-7,9(5H); 8-0-8.3(4H); 8.4(1H); 8.8(1H) and 9.5(1H)ppm.

Example 30 (S)-2-Phenyl-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-2-Phenyl-N-(3-phenylpropan-1-ol-2-yl)benzamide

2 g (10 mmol) of 2-phenylbenzoic acid were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 3a, affording2.1 g (64%) of the product.

b) (S)-2-Phenyl-N-(3-phenylpropan-1-al-2-yl)benzamide

1.0 g (3 mmol) of the intermediate 30a was oxidized by the method ofprocedure 21c. 0.4 g (40%) of the product was obtained.

¹H-NMR(CDCl₃): δ=2.9(1H); 3.0(1H); 4.7(1H); 5.9(1H); 6.9-7.7(14H) and9.4(1H)ppm.

Example 31(S)-2-(E-2-(Naphth-2-yl)-ethen-1-yl)-N-(3-phenylpropan-1-al-2-yl)benzamide

a) Ethyl 2-(E-2-(naphth-2-yl)-ethen-1-yl)benzoate

29.7 g (0.13 mol) of 2-vinylnaphthalene, 25 g (0.16 mol) of ethyl2-bromobenzoate, 22.5 ml (0.16 mol) of triethylamine, 0.54 g ofpalladium diacetate and 1.44 g of triphenylphosphine in 200 ml ofacetonitrile were heated to 100° C. for 20 h. The reaction mixture wasthen poured into water and the mixture was extracted repeatedly withethyl acetate. The organic phase was concentrated under reduced pressureand the residue was purified chromatographically on silica gel. 34 g(71%) of the product were obtained.

b) 2-(E-2-(Naphth-2-yl)-ethen-1-yl)benzoic acid

34 g (112.5 mmol) of the intermediate 31a were dissolved in 200 ml oftetrahydrofuran and treated with 9.5 g (168.7 mmol) of 80% strengthpotassium hydroxide dissolved in 150 ml of water. The reaction mixturewas heated under reflux for 10 h. The reaction mixture was thenacidified with concentrated hydrochloric acid and extracted with ethylacetate. The organic phase was washed with water, dried and concentratedunder reduced pressure. The residue was treated with a little ethylacetate and filtered off with suction. 23.8 g (78%) of the product wereobtained.

c)(S)-2-(E-2-(Naphth-2-yl)-ethen-1-yl)-N-(3-phenylpropan-1-ol-2-yl)benzamide

1 g (3.6 mmol) of the intermediate 31b and 0.55 g (3.6 mmol) of(S)-2-amino-3-phenyl-1-propanol were reacted by the method of procedure3c. 1.1 g (75%) of the product were obtained.

d)(S)-2-(E-2-(Naphth-2-yl)-ethen-1-yl)-N-(3-phenylpropan-1-al-2-yl)benzamide

0.9 g (2.2 mmol) of the intermediate 31c was oxidized by the method ofprocedure 21c. 0.57 g (66%) of the product was obtained.

MS(ESI): m/e=405 (M⁺).

Example 32(S)-2-(E-2-(3,4-Dimethoxyphenyl)-ethen-1-yl)-N-(3-phenylpropan-1-al-2-yl)benzamide

a) Ethyl 2-(E-2-(3,4-Dimethoxyphenyl)-ethen-1-yl)benzoate

5 g (30.5 mmol) of 3,4-dimethoxystyrene were reacted with ethyl2-bromobenzoate in dimethylformamide at 120° C. by the method ofprocedure 31a. 1.2 g (4%) [sic] of the product were obtained.

b) 2-(E-2-(3,4-Dimethoxyphenyl)-ethen-1-yl)benzoic acid

7 g (22 mmol) of the intermediate 32a were hydrolyzed with 4M aqueoussodium hydroxide solution by the method of procedure 31b. 6.2 g (98%) ofthe product were obtained.

c)(S)-2-(2-(3,4-Dimethoxyphenyl)-ethen-1-yl)-N-(3-phenylpropan-1-ol-2-yl)benzamide

1 g (3.5 mmol) of the intermediate 32b was reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a. 1.3 g(90%) of the product were obtained.

d)(S)-2-(E-2-(3,4-Dimethoxyphenyl)-ethen-1-yl)-N-(3-phenylpropan-1-al-2-yl)benzamide

1 g (2.4 mmol) of the intermediate 32c was oxidized by the method ofprocedure 21c. 1 g (100%) of the product was obtained.

¹H-NMR(D₆-DMSO): δ=2.9(1H); 3.2(1H); 3.8(6H); 4.5(1H); 6.9-7.6(12H);7.8(2H); 8.8(1H) and 9.7(1H)ppm.

Example 33(S)-6-Methyl-3-(2-naphthyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-2-Methyl-N-(3-phenylpropan-1-ol-2-yl)-5-nitrobenzamide

5 g (27.6 mmol) of 2-methyl-5-nitrobenzoic acid were reacted with 4.2 g(27.6 mmol) of (S)-2-amino-3-phenyl-1-propanol by the method ofprocedure 3c. 7.5 g (87%) of the product were obtained.

b) (S)-5-Amino-2-methyl-N-(3-phenylpropan-1-ol-2-yl)benzamide

6.3 g (20 mmol) of the intermediate 33a were dissolved in 150 ml ofethanol and hydrogenated after the addition of 0.5 g of palladium/carbon(10%). The mixture was then filtered and the filtrate was concentratedunder reduced pressure. 4.9 g of the product were obtained.

c)(S)-6-Methyl-3-(2-naphthyl)amido-N-(3-phenylpropan-1-ol-2-yl)benzamide

1 g (3.5 mmol) of the intermediate 33b was reacted with 2-naphthoylchloride by the method of procedure 3a. 1.2 g (78%) of the product wereobtained.

d)(S)-6-Methyl-3-(2-naphthyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

1 g (2.3 mmol) of the intermediate 33c was oxidized by the method ofprocedure 21c. 1.0 g (100%) of the product was obtained.

¹H-NMR(D₆-DMSO): δ=2.2(3H); 2.8(1H); 3.3(1H); 4.5(1H); 7.0-8.2(13H);8.6(2H); 8.8(1H); 7.7(1H) and 10.5(1H)ppm.

Example 34(S)-3-Methyl-4-(2-naphthyl)amido-N-(3-phenylpropan-1-al-2-yl)-benzamide

a) (S)-3-Methyl-N-(3-phenylpropan-1-ol-2-yl)-4-nitrobenzamide

5 g (27.6 mmol) of 3-methyl-4-nitrobenzoic acid were reacted with 4.2 g(27.6 mmol) of (S)-2-amino-3-phenyl-1-propanol by the method ofprocedure 3c. 7.1 g (82%) of the product were obtained.

b) (S)-4-Amino-3-methyl-N-(3-phenylpropan-1-ol-2-yl)benzamide

7 g (22.3 mmol) of the intermediate 34a were hydrogenated by the methodof procedure 33b. 5.6 g (89%) of the product were obtained.

c)(S)-3-Methyl-4-(2-naphthyl)amido-N-(3-phenylpropan-1-ol-2-yl)benzamide

1 g (3.5 mmol) of the intermediate 34b was reacted with 2-naphthoylchloride by the method of procedure 3a. 1.3 g (83%) of the product wereobtained.

d)(S)-3-Methyl-4-(2-naphthyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

1 g (2.3 mmol) of the intermediate 34c was oxidized by the method ofprocedure 21c. 0.95 g (96%) of the product was obtained.

MS(ESI): m/E=436(M⁺).

Example 35 (S)-4-Phenylsulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) Ethyl 4-phenylsulfonamidobenzoate

5 g (30.3 mmol) of ethyl 4-aminobenzoate were dissolved in 100 ml ofpyridine and admixed dropwise at 0° C. with 4.1 ml (31.8 mmol) ofbenzenesulfonyl chloride. The mixture was stirred for 3 h. The mixturewas then concentrated under reduced pressure and the residue wasrecrystallized from ethanol. 7.3 g (85%) of the product were obtained.

b) 4-Phenylsulfonamidobenzoic acid

7 g (22.9 mmol) of the intermediate 35a were hydrolyzed under refluxwith 4M aqueous sodium hydroxide solution by the method of procedure31b. 5.9 g (94%) of the product were obtained.

c) (S)-4-Phenylsulfonamido-N-(3-phenylpropan-1-ol-2-yl)benzamide

2 g (7.2 mmol) of the intermediate 35b were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a. 1.9 g(65%) of the product were obtained.

d) (S)-4-Phenylsulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

1 g (2.4 mmol) of the intermediate 35c was oxidized by the method ofprocedure 21c. 0.9 g (94%) of the product was obtained.

¹H-NMR(D₆-DMSO): =2.8(1H); 3.2(1H); 4.3(1H); 7.0-7.9(14H); 8.7(1H);9.5(1H) and 10.6(1H)ppm.

Example 36(S)-2-Methyl-5-(2-naphthyl)sulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) 2-Methyl-N-(3-phenylpropan-1-ol-2-yl)-5-nitrobenzamide

5 g (27.6 mmol) of 2-methyl-5-nitrobenzoic acid were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 7.5 g(87%) of the product were obtained.

b) 5-Amino-2-methyl-N-(3-phenylpropan-1-ol-2-yl)benzamide

6.3 g (20.4 mmol) of the intermediate 36a were hydrogenated by themethod of procedure 33b. 4.9 g (86%) of the product were obtained.

c)(S)-2-Methyl-5-(2-naphthyl)sulfonamido-N-(3-phenylpropan-1-ol-2-yl)benzamide

1 g (3.5 mmol) of the intermediate 36b was reacted with 2-naphthoylchloride by the method of procedure 4b. 1.2 g (73%) of the product wereobtained.

d)(S)-2-Methyl-5-(2-naphthyl)sulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

1 g (2.1 mmol) of the intermediate 36c was oxidized by the method ofprocedure 21c. 0.65 g (66%) of the product was obtained.

¹H-NMR(D₆-DMSO): δ=2.0(3H); 2.8(1H); 3.2(1H); 4.5(1H); 6.9-7.5(8H);7.6-7.9(3H); 7.9-8.2(3H); 8.3(1H); 8,5(1H); 9.5(1H) and 10.3(1H)ppm.

Example 37(S)-4-Methyl-3-(2-naphthyl)sulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) 3-Methyl-N-(3-phenylpropan-1-ol-2-yl )-4-nitrobenzamide

5 g (27.6 mmol) of 3-methyl-4-nitrobenzoic acid were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 7.1 g(82%) of the product were obtained.

b) 4-Amino-3-methyl-N-(3-phenylpropan-1-ol-2-yl)benzamide

7 g (22.3 mmol) of the intermediate 37a were hydrogenated by the methodof procedure 33b. 5.6 g (89%) of the product were obtained.

c)(S)-4-Methyl-3-(2-naphthyl)sulfonamido-N-(3-phenylpropan-1-ol-2-yl)benzamide

1.5 g (5.3 mmol) of the intermediate 37b were reacted with 2-naphthoylchloride by the method of procedure 35a. 1.4 g (56%) of the product wereobtained.

d)(S)-4-Methyl-3-(2-naphthyl)sulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

1.1 g (2.3 mmol) of the intermediate 37c were oxidized by the method ofprocedure 21c. 1.0 g (92%) of the product was obtained.

¹H-NMR(D₆-DMSO): δ=2.1(3H); 2.9(1H); 3.2(1H); 4.3(1H); 7.0-8.2(13H);8.2(2H); 8.7(1H); 9.5(1H) and 9.8(1H)ppm.

Example 38(S)-6-Methyl-3-phenylsulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

a)(S)-6-Methyl-3-phenylsulfonamido-N-(3-phenylpropan-1-ol-2-yl)benzamide

1 g (3.5 mmol) of the intermediate 36b was reacted with benzenesulfonylchloride by the method of procedure 35a. 1.2 g (83%) of the product wereobtained.

b)(S)-6-Methyl-3-phenylsulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

1 g (2.4 mmol) of the intermediate 38c was oxidized by the method ofprocedure 21c. 0.8 g of the product was obtained.

¹H-NMR(D₆-DMSO): δ=2.0(3H); 2.8(1H); 3.2(1H); 4.4(1H); 6.9-7.8(13H);8.6(1H); 9.5(1H) and 10.2(1H)ppm.

Example 39 (S)-3-Phenylsulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-N-(3-phenylpropan-1-ol-2-yl)-4-nitrobenzamide

5 g (33 mmol)of (S)-2-amino-3-phenyl-1-propanol were reacted with 6.1 g(33 mmol) of 3-nitrobenzoyl chloride by the method of procedure 10a. 9.2g (93%) of the product were obtained.

b) (S)-4-Amino-N-(3-phenylpropan-1-ol-2-yl)benzamide

9.1 g (30.3 mmol) of the intermediate 39a were hydrogenated by themethod of procedure 33b. 8.4 g (100%) of the product were obtained.

c) (S)-3-Phenylsulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

1 g (3.7 mmol) of the intermediate 39b was reacted with benzenesulfonylchloride by the method of procedure 35a. 0.72 g (48%) of the product wasobtained.

d) (S)-3-Phenylsulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

0.6 g (1.5 mmol) of the intermediate 39c was oxidized by the method ofprocedure 21c. 0.55 g (93%) of the product was obtained.

MS: m/e=408(M⁺).

Example 40(S)-4-(E-2-Naphtho-2-yl-1-ethenyl)-N-(3-phenylpropan-1-al-2-yl)benzamide

a) 4-(E-2-Naphtho-2-yl-1-ethenyl)benzoic acid

4.5 g (26.4 mmol) of 2-acetylnaphthalene and 4.3 g (26.4 [lacuna]) ofmethyl 4-formylbenzoate were dissolved in 100 ml of methanol and treatedwith 16 ml of 4M aqueous sodium hydroxide solution. The mixture wasstirred for about 1 h. A large volume of water was then added and themixture was stirred for a further 72 h. The mixture was then acidifiedwith concentrated hydrochloric acid whereupon a precipitate formed. Theprecipitate was filtered off with suction and recrystallized fromethanol. 7.2 g (90%) of the product were obtained.

b)(S)-4-(E-2-Naphtho-2-yl-1-ethenyl)-N-(-3-phenylpropan-1-ol-2-yl)benzamide

1.2 g (7.6 mmol) of (s)-2-amino-3-phenyl-1-propanol were reacted with2.3 g (7.6 mmol) of the intermediate 40a by the method of procedure 7a.2.1 g (64%) of the product were obtained.

(S)-4-(E-2-Naphtho-2-yl-1-ethenyl)-N-(3-phenylpropan-1-al-2-yl)benzamide

0.7 g (1.65 mmol) of the intermediate 40b was oxidized by the method ofprocedure 21c. 0.66 g (92%) of the product was obtained.

MS: m/e=433(M⁺).

Example 41(S)-3-(E-2-Naphtho-2-yl-1-ethenyl)-N-(3-phenylpropan-1-al-2-yl)benzamide

a) 4-(E-2-Naphtho-2-yl-1-ethenyl)benzoic acid

4.5 g (26.4 mmol) of 2-acetylnaphthalene were reacted with 4 g (26.4mmol) of 3-formylbenzoic acid by the method of procedure 40a. 7.4 g(93%) of the product were obtained.

b)(S)-3-(E-2-Naphtho-2-yl-1-ethenyl)-N-(3-phenylpropan-1-ol-2-yl)benzamide

0.6 g (4 mmol) of (S)-2-amino-3-phenyl-1-propanol was reacted with 1.2 g(4 mmol) of the intermediate 41a by the method of procedure 7a. 1.5 g(87%) of the product were obtained.

c)(S)-3-(E-2-Naphtho-2-yl-1-ethenyl)-N-(3-phenylpropan-1-al-2-yl)benzamide

1 g (2.3 mmol) of the intermediate 41b was oxidized by the method ofprocedure 21c. 0.91 g of the product was obtained.

MS: m/e=433(M⁺).

Example 42(S)-N-(4-Methylthio-1-butanal-2-yl)-3-(2-naphthylsulfonamido)benzamide

a)(S)-N-(4-Methylthio-1-butanol-2-yl)-3-(2-naphthylsulfonamido)benzamide

2 g (3.1 mmol) of 3-(2-naphthylsulfonamido)benzoic acid (intermediate22a) were reacted with (S)-2-amino-4-methylthio-1-butanol by the methodof procedure 7a, affording 1.6 g (59%) of the product.

b)(S)-N-(4-Methylthio-1-butanol-2-yl)-3-(2-naphthylsulfonamido)benzamide

1.0 g (2.5 mmol) of the intermediate 42a was oxidized by the method ofprocedure 21c. 0.74 g (75%) of the product was obtained.

MS: m/e=442(M⁺).

Example 43(S)-4-(2-Naphthyl)amido-2-(E-2-phenylethen-1-yl)-N-(3-phenylpropan-1-al-2-yl)benzamide

a) 2-Bromo-4-nitro-benzoic acid

75 g (0.35 mol) of 2-bromo-4-nitrotoluene, 12 ml of aliquot 336 and 39 g(0.47 mol) of sodium hydrogen sulfate in 1.5 l of water were heated to80° C. The mixture was stirred well and 183 g (1.16 mol) of potassiumpermanganate were then added a little at a time. The mixture was thenheated under reflux for 45 min. The mixture was filtered through CELITEand the filtrate was concentrated to about 700 ml under reducedpressure. The aqueous solution was acidified with concentratedhydrochloric acid, whereupon the product precipitated. 45 g (53%) of theproduct were obtained.

b) Ethyl 2-bromo-4-nitro-benzoate

44.5 g (0.18 mol) of the intermediate 43a were added to 450 ml ofethanol and treated carefully with 45 ml of concentrated sulfuric acid.The mixture was then heated under reflux for 4 h. The mixture was thenpoured into ice-water and the product was extracted with ethyl acetate.The organic phase was washed with aqueous sodium hydrogen sulfatesolution and water, dried and concentrated under reduced pressure. 50.4g (100%) of the product were obtained.

c) Ethyl 4-nitro-2-(E-2-phenylethen-1-yl)benzoate

50 g (0.18 mol) of the intermediate 43b were reacted with styrene indimethylformamide at reflux temperature by the method of procedure 31a.35 g (65%) of the product were obtained.

d) 4-Nitro-2-(E-2-phenylethen-1-yl)benzoic acid

35 g (0.12 mol) of the intermediate 43c were hydrolyzed with aqueoussodium hydroxide solution by the method of procedure 31b. 29 g (92%) ofthe product were obtained.

e)(S)-4-Nitro-2-(E-2-phenylethen-1-yl)-N-(3-phenylpropan-1-ol-2-yl)benzamide

5.6 g (37.1 mmol) of (S)-2-amino-3-phenyl-1-propanol were reacted with10 g (37.1 mmol) of the intermediate 43d by the method of procedure 7a.11.3 g (76%) of the product were obtained.

f)(S)-4-Amino-2-(E-2-phenylethen-1-yl)-N-(3-phenylpropan-1-ol-2-yl)benzamide

10 g (24.9 mmol) of the intermediate 43e were hydrogenated in 200 ml oftetrahydrofuran in the presence of 3 g of Raney nickel. The mixture wasthen filtered and the filtrate was concentrated under reduced pressure.Recrystallization from ethanol gave 6.2 g (69%) of the product.

g)(S)-4-(2-Naphthyl)amido-2-(E-2-phenylethen-1-yl)-N-(3-phenylpropan-1-ol-2-yl)benzamide

1 g (2.7 mmol) of the intermediate 43f was reacted with 2-naphthoylchloride by the method of procedure 10a. 1.2 g (86%) of the product wereobtained.

h)(S)-4-(2-Naphthyl)amido-2-(E-2-phenylethen-1-yl)-N-(3-phenylpropan-1-al-2-yl)benzamide

1.0 g (1.9 mmol) of the intermediate 43 g was oxidized by the method ofprocedure 21c. 0.75 g (76%) of the product was obtained.

MS: m/e=524(M⁺).

Example 44 (S)-3-(2-Naphthyl)sulfonylamido-N-(pentan-1-al-2-yl)benzamide

a) (S)-3-(2-Naphthyl)sulfonylamido-N-(pentan-1-ol-2-yl)benzamide

2 g (6.1 mmol) of 3(2-naphthylsulfonamido)benzoic acid (intermediate22a) were reacted with D,L-2-amino-1-pentanol by the method of procedure7a, affording 1.9 g (76%) of the product.

b) (S)-3-(2-Naphthyl)sulfonylamido-N-(pentan-1-al-2-yl)benzamide

1.3 g (3.2 mmol) of the intermediate 44a were oxidized by the method ofprocedure 21c. 1.3 g (100%) of the product were obtained.

¹H-NMR(D₆-DMSO): δ=0.9(3H); 1.1-1.9(4H); 4.1(1H); 7.1-8.1(10H); 8.3(1H);8.6(1H); 9.4(1H) and 10.5(1H)ppm.

Example 45 3-(2-Naphthyl) sulfonylamido-N-(butan-1-al-2-yl )benzamide

a) 3-(2-Naphthyl)sulfonylamido-N-(butan-1-ol-2-yl)benzamide

2 g (6.1 mmol) of 3-(2-naphthylsulfonamido)benzoic acid (intermediate22a) were reacted with D,L-2-amino-1-butanol by the method of procedure7a, affording 1.3 g (54%) of the product.

b) 3-(2-Naphthyl)sulfonylamido-N-(butan-1-al-2-yl)benzamide

1 g (2.5 mmol) of the intermediate 45a was oxidized by the method ofprocedure 21c. 0.55 g of the product was obtained.

¹H-NMR(D₆-DMSO): δ=1.0(3H); 1.7(1H); 1.9(1H); 4.1(1H); 7.1-8.1(9H);8.3(2H); 8.6(1H); 9.5(1H) and 10.6(1H)ppm.

Example 463-(2-Naphthyl)sulfonamido-N-(3-indol-3-ylpropan-1-al-2-yl)benzamide

a) 3-(2-Naphthyl)sulfonamido-N-(3-indol-3-ylpropan-1-ol-2-yl)benzamide

1 g (3.1 mmol) of 3(2-naphthylsulfonamido)benzoic acid (intermediate22a) was reacted with D,L-3-indol-3-ylpropan-1-ol by the method ofprocedure 7a, affording 0.9 g (60%) of the product.

b) 3-(2-Naphthyl)sulfonamido-N-(3-indol-3-ylpropan-1-al-2-yl)benzamide

0.8 g (1.6 mmol) of the intermediate 46a was oxidized by the method ofprocedure 21c. 0.71 g (90%) of the product was obtained.

MS: m/e=497(M⁺).

Example 47(S)-N-(3-Cyclohexylpropan-1-al-2-yl)-3-(2-naphthyl)sulfonamidobenzamide

a)(S)-N-(3-Cyclohexylpropan-1-al-2-yl)-3-(2-naphthyl)sulfonamidobenzamide

1.5 g (4.6 mmol) of 3-(2-naphthylsulfonamido)benzoic acid (intermediate22a) were reacted with (S)-2-amino-3-cyclohexylpropan-1-ol by the methodof procedure 7a, affording 1.8 g (77%) of the product.

b)(S)-N-(3-Cyclohexylpropan-1-al-2-yl)-3-(2-naphthyl)sulfonamidobenzamide

1.4 g (3 mmol) of the intermediate 47a were oxidized by the method ofprocedure 21c. 1.35 g (100%) of the product were obtained.

¹H-NMR(D₆-DMSO): δ=0.8-1.9(13H); 4.2(1H); 7.0-8.1(10H); 8.2(1H);8.6(1H); 9.3(1H) and 10.5(1H)ppm.

Example 48(S)-4-Nitro-2(E-phenyl-1-ethenyl)-N(3-phenylpropan-1-al-2-yl)benzamide[sic]

0.4 g (1 mmol) of(S)-4-nitro-2-(E-2-phenylethen-1-yl)-N-(3-phenylpropan-1-ol-2-yl)benzamide(intermediate 43e) was oxidized by the method of procedure 21c. 0.35 g(88%) of the product was obtained.

MS: m/e=(M⁺) [sic].

Example 49(S)-4-(2-Naphthylsulfonamido)methyl-N-(3-phenylpropan-1-al-2-yl)benzamide

a) 4-(2-Naphthylsulfonamido)methylbenzoic acid

3.8 g (25 mmol) of 4-(aminomethyl)benzoic acid were reacted with2-naphthalenesulfonyl chloride by the method of procedure 4b, affording6.1 g (72%) of the product.

b)(S)-4-(2-Naphthylsulfonamido)methyl-N-(3-phenylpropan-1-ol-2-yl)benzamide

3.1 g (9 mmol) of the intermediate 49a were reacted with(S)-2-amino-3-cyclohexylpropan-1-ol by the method of procedure 7a,affording 2.4 g (62%) of the product.

c)(S)-4-(2-Naphthylsulfonamido)methyl-N-(3-phenylpropan-1-al-2-yl)benzamide

1.6 g (3.6 mmol) of the intermediate 49b were oxidized by the method ofprocedure 21c. 1.0 g (64%) of the product was obtained.

¹H-NMR(D₆-DMSO): δ=2.9(1H); 3.3(1H); 4.02H); 4.5(1H); 7.0-8.5(17H);8.8(1H) and 9.5(1H)ppm.

Example 50(S)-6-Bromo-3-(2-naphthyl)sulfonylamido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) Ethyl 2-bromo-5-nitrobenzoate

22.9 g (0.1 mol) of ethyl 2-bromobenzoate were carefully introduced into55 ml of sulfuric acid. At 0° C., 16.5 ml of nitrating acid (prepared at0° C. from 5.5 ml of 98% strength nitric acid and 11 ml of 97% strengthsulfuric acid) were subsequently added dropwise and the mixture wasstirred for about 1 h. The reaction mixture was then carefully pouredinto ice-water. The precipitate was recrystallized from ethanol,yielding 17.7 g (64%) of the product.

b) Ethyl 5-amino-2-bromobenzoate

10 g (36 mmol) of the intermediate 50a were dissolved in 200 ml ofglacial acetic acid and heated to 80° C. 12 g (21.5 mmol) of iron powderwere then carefully (violent reaction) added a little at a time. Theprecipitate that formed was filtered off with suction and the filtratewas concentrated under reduced pressure. This residue was acidified withhydrochloric acid and extracted with ethyl acetate. The organic phasewas dried and concentrated under reduced pressure. 6 g (68%) of theproduct were obtained.

c) Ethyl 6-bromo-3-(2-naphthyl)sulfonylamidobenzoate

5.5 g (22.5 mmol) of the intermediate 50b were reacted with2-naphthylsulfonyl chloride by the method of procedure 4b. Afterchromatographic purification (eluent: toluene/ethanol=17/3), 7 g (72%)of the product were obtained.

d) 6-Bromo-3-(2-naphthyl)sulfonylamidobenzoic acid

3 g (6.9 mmol) of the intermediate 50c were hydrolyzed by the method ofprocedure 3b. 2.5 g (89%) of the product were obtained.

e)(S)-6-Bromo-3-(2-naphthyl)sulfonylamido-N-(3-phenylpropan-1-ol-2-yl)benzamide

1 g (2.5 mmol) of the intermediate 50d was reacted with(S)-2-amino-3-phenylpropan-1-ol by the method of procedure 7a, affording0.87 g (87%) of the product after chromatographic purification (eluent:ethyl acetate/n-heptane=2/1).

f)(S)-6-Bromo-3-(2-naphthyl)sulfonylamido-N-(3-phenylpropan-1-al-2-yl)benzamide

0.72 g (1.3 mmol) of the intermediate 50e was oxidized by the method ofprocedure 21c. 0.6 g (86%) of the product was obtained.

¹H-NMR(D₆-DMSO): δ=2.8(1H); 3.2(1H); 4.5(1H); 7.0-8.1(12H); 8.4(1H);8.9(1H); 9.6(1H) and 10.8(1H) ppm.

Example 51(S)-4-(2-Naphthyl)sulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

a) Ethyl 4-(2-naphthylsulfonamido)benzoate

10 g (60.5 mmol) of ethyl 4-aminobenzoate and 13.7 g (60.5 mmol) of2-naphthylsulfonyl chloride were reacted by the method of procedure 4b,affording 13.6 g (64%) of the product.

b) 4-(2-Naphthylsulfonamido)benzoic acid

13.2 g (37.1 mmol) of the intermediate 51a were hydrolyzed with lithiumhydroxide by the method of procedure 3b. 11.1 g (95%) of the productwere obtained.

c) (S)-4-(2-Naphthyl)sulfonamido-N-(3-phenylpropan-1-ol-2-yl)benzamide

1.5 g (4.6 mmol) of the intermediate 51b were reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a, affording1.7 g (81%) of the product.

d) (S)-3-(2-Naphthyl)sulfonamido-N-(3-phenylpropan-1-al-2-yl)benzamide

1.4 g (3 mmol) of the intermediate 22b were oxidized with dimeth [sic]sulfoxide/trifluoroacetic anhydride by the method of procedure 1c. Afterchromatographic purification (eluent: toluene/acetone=1/1), 0.12 g ofthe product was obtained.

¹H-NMR(D₆-DMSO): δ=2.9(1H); 3.2(1H); 4.3(1H); 7.0-8.1(14H); 8.4(2H);8.6(1H); 9.5(1H) and 11.7(1H)ppm.

Example 52(S)-2-(2-Naphthylmethyl)-N-(3-phenylpropan-1-al-2-yl)benzamide

a) 4,4-Dimethyl-2-(2-(naphth-2-yl-hydroxymethyl)phenyl)-2-oxazolin

At −78° C., 104 ml of a 1.6M solution of butyl lithium were slowly addeddropwise to 25 g (0.14 mol) of 4,4-dimethyl-2-phenyl-2-oxazolin and 0.1g of triphenylmethane in 400 ml of anhydrous tetrahydrofuran. Themixture was stirred for 1 h. The mixture was then allowed to warm to−30° C. and a solution of 20.3 g (0.13 mol) of 2-naphthaldehyde in 200ml of anhydrous tetrahydrofuran was added dropwise. Stirring wascontinued for about 1 h at −20 to −30° C. The reaction solution was thenallowed to warm to room temperature and the solvent was removed underreduced pressure. The residue was introduced into ice-water which wasthen extracted with ether. The organic phase was dried and concentratedunder reduced pressure. This residue was purified chromatographically(eluent: n-heptane/acetone=40/3), affording 25.3 g (54%) of the product.

b) 3-Napth-2-ylphthalide

22 g (66 mmol) of the intermediate 52a were heated under reflux in amixture of 250 ml of ethanol and 100 ml of 1M hydrochloric acid for 2 h.The ethanol was then removed under reduced pressure and the resultingprecipitate was filtered off with suction. 16.4 g (95%) of the productwere obtained.

c) 2-Naphth-2-yl-benzoic acid

16 g (61.5 mmol) of the intermediate 52b were dissolved in a mixture of100 ml of tetrahydrofuran and 250 ml of ethanol and hydrogenated afterthe addition of 5 g of palladium/barium sulfate. The mixture was thenfiltered and the filtrate was concentrated under reduced pressure. Theresidue was recrystallized from toluene, affording 13.6 g (85%) of theproduct.

d) (S)-2-(2-Naphthylmethyl)-N-(3-phenylpropan-1-ol-2-yl)benzamide

1 g (3.8 mmol) of the intermediate 51c was reacted with(S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a, affording1.2 g (80%) of the product.

e) (S)-2-(2-Naphthylmethyl)-N-(3-phenylpropan-1-al-2-yl)benzamide

1 g (2.5 mmol) of the intermediate 51d was oxidized by the method ofprocedure 21c. 1.0 g (89%) of the product was obtained.

¹H-NMR(D₆-DMSO): δ=2.8(1H); 3.2(1H); 4.1(12H); 4.4(1H); 7.0-8.0(16H);8.8(1H) and 9.4(1H)ppm.

Example 53(S)-4-Acetamido-2-(E-2-phenyl-1-ethenyl)-N-(3-phenylpropan-1-al-2-yl)benzamide

a)(S)-4-Acetamido-2-(E-2-phenyl-1-ethenyl)-N-(3-phenylpropan-1-ol-2-yl)benzamide

1 g (2.7 mmol) of(S)-4-amino-2(E-2-phenylethen-1-yl)-N-(3-phenylpropan-1-ol-2-yl)benzamide(intermediate 43f) was suspended in 50 ml of tetrahydrofuran and mixedwith 0.25 ml (2.7 mmol) of acetic anhydride at 100° C. The mixture wasstirred for 16 h. The reaction was then concentrated under reducedpressure and the residue was recrystallized from ethanol. 0.78 g (71%)of the product was obtained.

b)(S)-4-Acetamido-2-(E-2-phenyl-1-ethenyl)-N-(3-phenylpropan-1-al-2-yl)benzamide

0.65 g (1.6 mmol) of the intermediate 53a was oxidized with [lacuna] bythe method of procedure 21c. 0.5 g (77%) of the product was obtained.

¹H-NMR(D₆-DMSO): δ=2.9(1H); 3.2(1H); 4.6(1H); 7-7.7(14H); 8.0(1H);8.8(1H); 9.7(1H) and 10.1(1H) ppm.

Example 54(S)-3-(8-Quinolinylsulfonamido)-N-(3-phenylpropan-1-al-2-yl)benzamide

a) (S)-3-(8-Quinolinylsulfonamido)-N-(3-phenylpropan-1-ol-2-yl)benzamide

1.2 g (4.6 mmol) of (S)-4-amino-N-(3-phenylpropan-1-ol-2-yl)benzamide(intermediate 39b) were reacted with 8-guinolinesulfonyl chloride by themethod of procedure 10a. 1 g of the product was obtained.

b) (S)-3-(8-Quinolinylsulfonamido)-N-(3-phenylpropan-1-al-2-yl)benzamide

0.9 g (1.95 mmol) of the intermediate 54a was oxidized with [lacuna] bythe method of procedure 21c. 0.69 g (77%) of the product was obtained.

¹H-NMR(D₆-DMSO): δ=2.9(1H); 3.2(1H); 4.3(1H); 7.0-7.9(11H); 8.2(1H);8.3(1H); 8.5(1H); 8.7(1H); 9.1(1H); 9.5(1H) and 10.2(1H) ppm.

Similarly to the abovementioned examples, further compounds according tothe invention were prepared:

Example 55(S)-4-(2-Fluoro-4-pyridylphenyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

1H-NMR(CF₃COOD): δ=3.2(2H); 4.8(1H); 6.7(1H); 7.2-8.4(14H); 9.0(2H) and11.8(1H) ppm.

Example 56(S)-2-Fluoro-N-(3-phenylpropan-1-al-2-yl)-4-(4-pyridyl)benzamide

1H-NMR(CDCl₃): δ=3.3(2H); 4.95(1H); 7.2-7.6(10H); 8.2(1H); 8.7(1H) and9.7(1H) ppm.

Example 57 N-(Butan-1-al-2-yl)-3-(8-quinolinyl)sulfonamidobenzamide

MS: m/e=441(M+).

Example 58 N-(Butan-1-al-2-yl)-4-(8-quinolinyl)sulfonamidobenzamide

MS: m/e=397(M+).

Example 59 3-(8-Quinolinyl)sulfonamido-N-(pentan-1-al-2-yl)benzamide

1H-NMR(CDCl₃): δ=1.3(3H); 1.75(2H); 2.0(2H); 4.7(1H); 6.55(1H);7.2-7.7(6H); 8.0(1H); 8.3(2H); 8.7(broad); 9.1(1H) and 9.7(1H) ppm.

Example 60 4-(8-Quinolinyl)sulfonamido-N-(pentan-1-al-2-yl)benzamide

1H-NMR(D₆-DMSO): δ=1.2(3H); 1.4(2H); 1.75(2H); 4.1(1H); 7.15(2H);7.5-7.8(4H); 8.3(1H); 8.4-8.7(3H); 9.1(1H); 9.3(1H) and 10.5(1H) ppm.

Example 61 N-(Pentan-1-al-2-yl)-2-(E-2-pyrid-2-ylethen-1-yl)benzamidehydrochloride

1H-NMR(D₆-DMSO): δ=0.9(3H); 1.4(2H); 1.6(1H); 1.8(1H); 4.4(1H);7.3-8.5(9H); 8.7(1H); 8.9(1H) and 9.6(1H) ppm.

Example 62(S)-N-(4-Methylpentan-1-al-2-yl)-2-(E-2-pyrid-2-ylethen-1-yl)benzamidehydrochloride

1H-NMR(D₆-DMSO): δ=0.9(3H); 1.5-1.9(3H); 4.4(1H); 7.4-8.2(9H); 8.4(1H);8.8(1H); 9.0(1H) and 9.7(1H) ppm.

Beispiel 63 (S)-N-(4-Methylthiobutan-1-al-2-yl)-2-(E-2-pyrid-2-ylethen-1-yl)benzamide hydrochloride

1H-NMR(D₆-DMSO): δ=2.0(1H); 2.3(1H); 2.55(3H); 2.7-3.0(2H); 4.4(1H);7.5-8.5(10H); 8.8(1H); 9.2(1H); and 9.7(1H) ppm.

Example 64 N-(Butan-1-al-2-yl)-2-(E-2-pyrid-2-ylethen-1-yl)benzamidehydrochloride

MS: m/e=294(M+).

Example 65(S)-N-(3-Phenylprop-1-al-2-yl)-2-(E-2-pyrid-4-ylethen-1-yl)benzamide

1H-NMR(CDCl₃): δ=3.3(2H); 5.05(1H); 6.55(1H); 6.9-7.8(13H); 8.5(2H) and9.8(1H) ppm.

Example 66 (S)-N-(3-Phenylprop-1-al-2-yl)-4-(2-pyridyl)benzamide

1H-NMR(D₆-DMSO): δ=3.0(1H); 3.3(1H); 4.5(1H); 7.1(1H); 7.25(3H);7.35(1H); 7.9-8.2(6H); 8.7(1H); 9.0(1H) and 9.7(1H) ppm.

Example 67(S)-N-(3-Phenylprop-1-al-2-yl)-2-(E-2-pyrid-2-ylethen-1-yl)benzamide

1H-NMR(CF₃COOD): δ=3.25(1H); 3.4(1H); 4.9(1H) and 7.2-8.8(16H) ppm.

Example 68(S)-N-(3-Phenylprop-1-al-2-yl)-3-(3-pyridylsulfonamido)benzamide

1H-NMR(D₆-DMSO): δ=2.9(1H); 3.05(1H); 4.6(1H); 7.0-7.7(13H); 8.8(1H) and10.0(1H) ppm.

Example 69(S)-2-Methyl-N-(3-phenylprop-1-al-2-yl)-5-(3-pyridylsulfonamido)benzamide

1H-NMR(D₆-DMSO): δ=2.0(3H); 2.8(1H); 3.25(1H); 4.5(1H); 6.9-7.4(7H);7.6(1H); 8.1(1H); 8.6-8.9(3H); 9.6(1H) and 10.5(1ppm.

Example 70 N-(Butan-1-al-2-yl)-2-(E-2-pyrid-2-ylethen-1-yl)benzamidehydrochloride

1H-NMR(CDCl₃): δ=1.0(3H); 1.8(1H); 2.1(1H); 4.8(1H); 6.5(1H);6.9-7.9(6H), 8.5(2H) and 9.7(1H) ppm.

Example 71(S)-4-Methanesulfonamido-2-(E-2-phenylethen-1-yl)-N-(3-phenylprop-1-al-2-yl)benzamide

MS: m/e=448(M+).

Example 726-Methyl-N-(pentan-1-al-2-yl)-3-(3-pyridylsulfonamido)benzamide

MS: m/e=375(M+).

Example 73 (S)-N-(3-Phenylprop-1-al-2-yl)-4-(4-pyridyl)benzamide

1H-NMR(CDCl₃): δ=3.35(2H); 5.O(1H); 6.8(1H); 7.2-7.9(11H); 8.7(2H) and9.75(1H) ppm.

Example 74 N-(Pentan-1-al-2-yl)-2-(2-pyridylmethoxy)benzamide xmethanesulfonic acid

1H-NMR(CDCl₃): δ=0.9(3H); 1.3(2H); 1.7(1H); 1.9(1H); 4.7(1H); 5.3(2H);7.0-7.9(6H); 8.2(1H); 8.6(1H); 8.9(1H); and 9.6(1H)ppm.

Example 75 N-(Pentan-1-al-2-yl)-2-(3-pyridylmethoxy)benzamide xmethanesulfonic acid

MS: m/e=312(M+).

Example 76 N-(Pentan-1-al-2-yl)-2-(E-2-pyrid-4-ylethen-1-yl)benzamide

1H-NMR(D₆-DMSO): δ=1.0(3H); 1.4(2H),; 1.7(1H); 2.1(1H); 4.5(1H);6.5(1H); 6.9-7.8(6H); 8.5(2H) and 9.7(1H) ppm.

Example 77 N-(Butan-1-al-2-yl)-2-(4-pyridylmethoxy)benzamide

1H-NMR(CDCl₃): δ=0.8(3H); 1.7(1H); 2.0(1H); 4.7(1H); 5.25(2H);7.0-7.6(5H); 8.2(1H); 8.3(1H); 8.6(1H) and 9.6(1H) ppm.

Example 78 N-(Hexan-1-al-2-yl)-2-(E-2-pyrid-2-ylethen-1-yl)benzamidehydrochloride

MS: m/e=322(M+).

Example 79(S)-4-(Quinolin-2-yl)thiomethyl-N-(3-phenylpropan-1-al-2-yl)benzamide xfumaric acid

1H-NMR(D₆-DMSO): δ=2.8-3.0(1H); 3.2-3.4(1H); 4.5(1H); 4.6(2H); 6.6(2H);7.0-8.2(13H); 8.8(1H) and 9.5(1H) ppm.

Example 80 4-(Quinolin-2-yl)thiomethyl-N-(3-pentan-1-al-2-yl)benzamide

1H-NMR(D₆-DMSO): δ=0.9(3H); 1.2-1.9(4H); 4.2(1H); 4.7(2H); 7.3-8.2(10H);8.8(1H) and 9.5(1H) ppm.

Example 81 2-(2-Quinolinylmethoxy)-N-(pentan-1-al-2-yl)benzamide

1H-NMR(D₆-DMSO): δ=0.7(3H); 1.2(2H); 1.3-1.8(2H); 4.3(1H); 5.5(2H);7.0-8.0(9H); 8.4(1H); 8.8(1H) and 9.5(1H) ppm.

Example 82N-(3-Pentan-1-al-2-yl)-4-(7-trifluoromethylquinolin-4-yl)thiomethylbenzamide

1H-NMR(D₆-DMSO): δ=0.9(3H); 1.2-1.9(4H); 4.2(1H); 4.6(2H); 7.6(3H);7.9(3H); 8.3(2H); 8.8(2H) and 9.5(1H) ppm.

Example 83(S)-4-(E-2-Isonicotinoyl-1-ethenyl)-N-(3-phenylpropan-1-al-2-yl)benzamidex fumaric acid

1H-NMR(D₆-DMSO): δ=2.7-3.0(2H); 4.2(1H); 6.7(2H); 7.25(5H);7.75-8.1(8H); 8.3(2H); 8.8(2H); and 9.5(1H) ppm.

Example 84(S)-4-Methoxy-3-(E-2-phenyl-1-ethenyl)amido-N-(3-phenylpropan-1-al-2-yl)benzamide

1H-NMR(D₆-DMSO): δ=2.9-3.1(1H); 3.25(1H); 4.0(3H); 4.5(1H);7.1-7.7(14H); 8.6(1H); 8.8(1H); 9.5(1H) and 9.6(1H) ppm.

Example 85 4-(E-2-Isonicotinoyl-1-ethenyl)-N-(pentan-1-al-2-yl)benzamide

1H-NMR(D₆-DMSO): δ=1.0(3H); 1.25-2.0(4H); 4.3(1H); 7.9-8.2(8H); 8.9(2H);9.0(1H) and 9.6(1H) ppm.

Example 86(S)-4-Methoxy-3-(E-2-phenyl-1-ethenyl)amido-N-(pentan-1-al-2-yl)benzamide

1H-NMR(D₆-DMSO): δ=1.0(3H); 1.25-2.0(4H); 4.0(3H); 4.25(1H);7.1-7.75(10H); 8.6(1H); 8.75(1H) and 9.5(1H) ppm.

We claim:
 1. A benzamidoaldehyde of the formula I

or a tautomeric or isomeric form or physiologically acceptable saltthereof, where: R¹ is phenyl, naphthalene, quinoline, isoquinoline,tetrahydroquinoline, tetrahydroisoquinoline, pyridine, pyrimidine,pyrazine, pyridazine, quinazoline, quinoxaline, thiophene,benzothiophene, benzofuran, furan or indole, where the aromatic andheteroaromatic rings may be substituted by up to three radicals R⁴, R²is hydrogen, chlorine, bromine, fluorine, phenyl with or withoutsubstitution by a C₁-C₄-hydrocarbon radical, —NHCO-C₁-C₄-alkyl, —NHCOPh,—NHCO-naphthyl, —NHSO₂-C₁₋₄-alkyl, —COO-C₁₋₄-alkyl, —CONH₂, COOH,—O-C₁₋₄-alkyl, —CO—NH-C₁₋₄-alkyl, NO₂ or NH₂, R³ is a C₁-C₆-hydrocarbonradical, which may also carry a cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, indolyl, phenyl, pyridine or naphthyl ring, itbeing possible for the rings in turn to be substituted by one or tworadicals R⁴, or is an —SCH₃ radical, R⁴ is C₁-C₄-alkyl, —O-C₁-C₄-alkyl,OH, Cl, F, Br, I, CF₃, NO₂, NH₂, CN, COOH, COO-C₁-C₄-alkyl,—NHCO-C₁-C₄-alkyl, —NHCOPh, —NHSO₂-C₁-C₄-alkyl, —NHSO₂-Ph,—(CH₂)_(n)—NR⁵R⁶ (R⁵ and R⁶ are identical or different and are eachhydrogen, C₁₋₄-alkyl or together are a ring), —SO₂-C₁-C₄-alkyl or—SO₂Ph, X is —(CH₂)_(m)—, —(CH₂)_(m)—O—(CH₂)_(o)—,—(CH₂)_(m)—S—(CH₂)_(o)—, —(CH₂)_(m)—SO—(CH₂)_(o)—,—(CH₂)_(m)—SO₂—(CH₂)_(o)—, —CH═CH—, —C≡C—, —CO—CH═CH—, —CH═CH—CO—,—(CH₂)_(m)—CO—(CH₂)_(o)—, —(CH₂)_(m)—NR⁵CO—(CH₂)_(o)—,—(CH₂)_(m)—CONR⁵—(CH₂)_(o)—, —(CH₂)_(m)—NHSO₂—(CH₂)_(o)—,—(CH₂)_(m)—SO₂NH—(CH₂)_(o)—, NH—CO—CH═CH—, —CH═CH—CO—NH— or n is thenumber 1 or 2, m is the number 0, 1, 2, 3 or 4, except that when X is—(CH₂)_(m)—, m is the number 1, 2, 3 or 4, and o is the nurmber 0, 1, 2,3 or 4, except that when R¹ is phenyl and X is —O—(CH₂)_(o)—, o is thenumber 1, 2, 3 or
 4. 2. A benzamide of the formula I as claimed in claim1, where R² is hydrogen, C₁-C₄-alkyl, methoxy, fluorine, chlorine orbromine, R³ is —CH₂-phenyl, —CH₂-cyclohexyl or —CH₂-indolyl, which maybe substituted by R⁴, and R¹, X, n, m and o are each as defined in claim1.
 3. A drug preparation for oral, parenteral or intraperitonaladministration, comprising at least one benzamidoaldehyde of the formulaI as claimed in claim
 1. 4. A method of inhibiting cysteine protease inan animal comprising administering to said animal a cysteine proteaseinhibiting amount of a benzamidoaldehyde of the formula I as claimed inclaim
 1. 5. The method of claim 4 wherein the animal suffers from aneurodegenerative disorder and/or neuronal damage.
 6. The method ofclaim 4 wherein the animal suffers from a neurodegenerative disorderand/or neuronal damage caused by ischemia, trauma or massivehemorrhages.
 7. The method of claim 4 wherein the animal suffers from acerebral vascular accident and/or craniocerebral trauma.
 8. The methodof claim 4 wherein the animal suffers from Alzheimer's disease orHuntingdon's disease.
 9. The method of of claim 4 wherein the animalsuffers from epilepsy.
 10. The method of claim 4 wherein the animalsuffers from damage to the heart after myocardial ischemia, damage to akidney after renal ischemia, damage to a skeletal muscle, musculardystrophy, damage caused by the proliferation of smooth muscles cells,coronal or cerebral vasospasm, a cataract of an eve and/or restenosis ofa blood vessel after angioplasty.
 11. The method of claim 4 wherein theanimal suffers from a tumor and its metastasis comprising.
 12. Themethod of claim 4 wherein the animal suffers from an increasedinterleukin-1 level.
 13. The method of claim 4 wherein the animalssuffers from an immunological disorder.
 14. The method of claim 4wherein the animal suffers from inflammation and/or a rheumaticdisorder.